Novel benzodioxole piperazine compounds

ABSTRACT

The present invention is concerned with novel dual modulators of the 5-HT 2A  and D 3  receptors of formula (I) 
     
       
         
         
             
             
         
       
     
     wherein n, Y, R 1 , R 2 , R 3 , and R 4  are as described herein, as well as pharmaceutically acceptable salts and esters thereof. Further the present invention is concerned with the manufacture of the compounds of formula (I), pharmaceutical compositions containing them and their use as pharmaceutical agents.

PRIORITY TO RELATED APPLICATION(S)

This application claims the benefit of European Patent Application No. 11154780.8, filed Feb. 17, 2011, which is hereby incorporated by reference in its entirety.

BACKGROUND OF THE INVENTION

Psychotic disorders encompass a variety of diseases, which include schizophrenia, positive, negative and/or cognitive symptoms associated with schizophrenia, schizoaffective disorders, bipolar disease, mania, psychotic depression, and other psychoses involving paranoia and delusions.

In particular schizophrenia is characterized by complex symptomatology including positive symptoms, (i.e. delusions and hallucinations), and negative symptoms, (i.e. anhedonia, restricted fluency and productivity of thought and speech). In addition it is now well recognized that cognitive impairment is the third major diagnostic category of schizophrenia, characterized by loss in working memory as well as other deficits. Other symptoms include aggressiveness, depression and anxiety (Stahl, S. M., Essential Psychopharmacology. Neuroscientific Basis and Practical Applications (2000) 2^(nd) edition, Cambridge University Press, Cambridge, UK).

Dopamine, a major catecholamine neurotransmitter, is involved in the regulation of a variety of functions which include emotion, cognition, motor functions, and positive reinforcement. The biological activities of dopamine are mediated through G protein-coupled receptors (GPCRs) and in human, five different dopamine receptors D₁-D₅ have been identified, where the D₂-like receptors (D₂, D₃ and D₄) couple to the G-protein G_(aI). The D₃ dopamine receptor is most highly expressed in the nucleus accumbens and is proposed to modulate the mesolimbic pathway consisting of neuronal projections from the ventral tegmental area, hippocampus and amygdala to the nucleus accumbens, which projects to the prefrontal and cingulate cortices as well as various thalamic nuclei. The limbic circuit is thought to be important for emotional behavior and thus D₃ receptor antagonists are proposed to modulate psychotic symptoms such as hallucinations, delusions and thought disorder (Joyce J. N., Millan M. J., Drug Discovery Today (2005) 10:917-925). In addition, it has been reported that drug naive schizophrenic patients show altered levels of D₃ receptor expression (Gurevich E. V. et al., Arch. Gen. Psychiatry (1997) 54, 225-232) and dopamine release (Laruelle M., Presentation at Institut de Recherches Internationales Servier Workshop on Schizophrenia: Pathological Bases and Mechanisms of Antipsychotic Action, Chicago, Ill., 2000), indicating that a disturbed homeostasis of dopamine plays an important role in the etiology of schizophrenic symptoms.

The neurotransmitter serotonin (5-Hydroxytryptamine; 5-HT) is implicated in several psychiatric conditions including schizophrenia (Kandel E. R. et al. (eds.), Principles of Neural Science (2000) 3^(rd) edition, Appleton & Lange, Norwalk, Conn.). The involvement of serotonin in psychotic disorders is suggested by multiple studies which include treatment in humans with the psychotropic drug Lysergic acid (LSD; a serotonin agonist) which can induce schizophrenia-like symptoms such as hallucinations (Leikin J. B. et al., Med. Toxicol. Adverse Drug Exp. (1989) 4:324-350). Furthermore, altered brain distribution of serotonin receptors as well as an altered serotonergic tone, have been detected in schizophrenic patients (Harrison P. J., Br. J. Psychiatry Suppl. (1999) 38:12-22).

In mammals, serotonin exerts its biological activities through a family of 14 5-HT GPCRs. The 5-HT_(2A) receptor is most prominently expressed in the prefrontal cortex and at lower levels in the basal ganglia and the hippocampus in human brain, and is coupled predominantly to the G-protein Gαq. Genetic linkage studies of a 5-HT_(2A) polymorph to schizophrenia (Spurlock G. et al., Mol. Psychiatry. (1998) 3:42-49), as well as responsiveness to antipsychotic drugs (Arranz, M. J. et al., Lancet (2000) 355:1615-1616), further suggest a role for the 5-HT_(2A) receptor both in the treatment and pathology of psychosis. In addition, dopaminergic neurotransmission appears to be under the afferent regulation of the 5-HT_(2A) receptor (Porras G. et al., Neuropsychopharmacology (2002) 26:311-324). Overall 5-HT_(2A) receptor antagonists are proposed to be suitable for the treatment of disorders associated with dysfunctional dopaminergic systems. Moreover, 5-HT_(2A) receptor antagonism has been recognized as beneficial for the treatment of psychosis (de Angelis L., Curr. Opin. Investig. Drugs (2002) 3:106-112).

The D₃ and 5-HT_(2A) receptors besides the mentioned psychotic disorders are further reported to be linked to other psychoses including paranoia and delusions (Reavill C. et al., JPET (2000) 294:1154-1165; Harrison P. J., Br. J. Psychiatry Suppl. (1999) 38:12-22), to drug dependency, abuse and withdrawal (Vorel S. R. et al., J. Neurosci. (2002) 22:9595-9603; Campos A. C. et al., Soc. Neurosci. Abstr., (2003) 322:8; Ashby C. R. et al., Synapse (2003) 48:154-156), attention deficit hyperactivity disorders (ADHD) (Retz W. et al., J. Neural. Transm. (2003) 110:531-572; Levitan R. D. et al., J. Affective Disorder (2002) 71:229-233), as well as to anxiety and depression (Reavill C. et al., JPET (2000) 294:1154-1165; Drescher K. et al. Am. Soc. Neurosci. (2002) 894:6).

Currently used medications to treat schizophrenia, bipolar mania and other psychoses, include both typical (D₂/D₃ preferring) or the more recent atypicals, which exhibit polypharmacology interacting at multiple receptors (e.g., D₁, D₂, D₃, D₄, 5-HT_(1A), 5-HT_(2A), 5-HT_(2C), H₁, M₁, M₂, M₄, etc.) (Roth B. L. et al., Nat. Rev. Drug Discov. (2004) 3:353-359). These antipsychotics, although relatively successful (some patients exhibit treatment resistance) at treating the positive symptoms of schizophrenia, are less effective at treating negative symptoms, cognitive deficits, and associated depression and anxiety, all of which lead to reduced patient quality of life and socioeconomic problems. Furthermore, patient compliance is compromised by prevalent side effects such as weight gain, extrapyramidal symptoms (EPS), and cardiovascular effects (Lieberman J. A. et al., N. Engl. J. Med. (2005) 353:1209-1223).

Antipsychotic drug treatment has frequently been complicated by serious side effects of widespread D₂ antagonism, notably an extrapyramidal or parkinsonian syndrome caused by antagonism of the dopaminergic projection from substantia nigra to corpus striatum. D₂ receptor blockade induces catalepsy and has been associated with negative effects against cognition. Also preferential blockade of D₃ vs. D₂ receptors, preserves and/or enhances cognitive function, and increases frontocortical cholinergic transmission. (Joyce J. N., Millan M. J., Drug Discovery Today (2005) 10:917-925, Moore N. A. et al., European Journal of Pharmacology (1993) 237:1-7; Barth V. N., Typical and atypical antipsychotics: Relationships between rat in vivo dopamine D(2) receptor occupancy assessed using LC/MS and changes in neurochemistry and catalepsy. Dissertation Indiana University (2006); Millan M. J. et al., Fr. Journal of Pharmacology and Experimental Therapeutics (2008) 324:1212-1226; Wiecki TV. et al., Psychopharmacology (2009) 204:265-277).

The typical antipsychotic agents on the market today display D₂ antagonism, and most have extrapyramidal side effects (EPS) such as pseudoparkinsonism and tardive dyskinesia (Howard H. R., Seeger T. F., Annual Reports in Medicinal Chemistry (1993) 28:39). It has been shown by selective binding experiments that D₂ receptors are more concentrated in the striatal regions of the brain, which are responsible for locomotor control than in the limbic regions which are responsible for thought processes. D₃ receptors are more concentrated in the limbic than in the striatal regions. It is therefore believed that selective D₃ ligands may relieve symptoms of schizophrenia without causing the EPS associated with blockade of D₂ receptors (Gackenheimer S. L. et al., J. Pharmacol. Exp. Ther. (1995) 274:1558, Belliotti T. R., Bioorg. Med. Chem. Lett. (1997) 7:2403).

SUMMARY OF THE INVENTION

The present invention is concerned with dual modulators of the 5-HT_(2A) and D₃ receptors, their manufacture, pharmaceutical compositions containing them and their use as pharmaceutical agents.

In particular, the present invention provides compounds of formula (I)

wherein R¹, R², R³, R⁴, n and Y are as described herein, and pharmaceutically acceptable salts and esters thereof.

The compounds of the invention and their pharmaceutically acceptable salts have high affinity and selectivity for both, the dopamine D₃ and serotonin 5-HT_(2A) receptors and are effective, alone or in combination with other drugs, in the treatment or prevention of psychotic disorders, as well as other diseases such as depression, anxiety, drug addiction, attention deficit hyperactivity disorders, dementia and memory impairment, while exhibiting fewer associated side effects.

DETAILED DESCRIPTION OF THE INVENTION

Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of the invention, suitable methods and materials are described below.

All publications, patent applications, patents, and other references mentioned herein are incorporated by reference in their entirety.

The nomenclature used in this Application is based on IUPAC systematic nomenclature, unless indicated otherwise.

Any open valency appearing on a carbon, oxygen, sulfur or nitrogen atom in the structures herein indicates the presence of a hydrogen, unless indicated otherwise.

The definitions described herein apply irrespective of whether the terms in question appear alone or in combination. It is contemplated that the definitions described herein can be appended to form chemically-relevant combinations, such as e.g. “heterocycloalkyl-aryl”, “haloalkyl-heteroaryl”, “aryl-alkyl-heterocycloalkyl”, or “alkoxy-alkyl”. The last member of the combination is a radical which is substituted by the other members of the combination in inverse order.

When indicating the number of substituents, the term “one or more” refers to the range from one substituent to the highest possible number of substitution, i.e. replacement of one hydrogen up to replacement of all hydrogens by substituents.

The term “optional” or “optionally” denotes that a subsequently described event or circumstance may, but need not occur, and that the description includes instances where the event or circumstance occurs and instances in which it does not.

The term “substituent” denotes an atom or a group of atoms replacing a hydrogen atom on the parent molecule.

The term “substituted” denotes that a specified group bears one or more substituents. Where any group can carry multiple substituents and a variety of possible substituents is provided, the substituents are independently selected and need not to be the same. The term “unsubstituted” means that the specified group bears no substituents. The term “optionally substituted” means that the specified group is unsubstituted or substituted by one or more substituents, independently chosen from the group of possible substituents. When indicating the number of substituents, the term “one or more” means from one substituent to the highest possible number of substitution, i.e. replacement of one hydrogen up to replacement of all hydrogens by substituents.

The term “compound(s) of this invention” and “compound(s) of the present invention” refers to compounds of formula (I) and stereoisomers, tautomers, solvates, and salts (e.g., pharmaceutically acceptable salts) thereof.

It will be appreciated, that the compounds of present invention can be derivatized at functional groups to provide derivatives which are capable of conversion back to the parent compound in vivo. Physiologically acceptable and metabolically labile derivatives, which are capable of producing the parent compounds of present invention in vivo are also within the scope of this invention.

The term “pharmaceutically acceptable esters” denotes derivatives of the compounds of present invention, in which a carboxy group has been converted to an ester, wherein carboxy group means —C(O)O—. Methyl-, ethyl-, methoxymethyl-, methylthiomethyl-, and pivaloyloxymethylesters are examples of such suitable esters. The term “pharmaceutically acceptable esters” furthermore embraces derivatives of the compounds of present invention in which hydroxy groups have been converted to the corresponding esters with inorganic or organic acids such as nitric acid, sulfuric acid, phosphoric acid, citric acid, formic acid, maleic acid, acetic acid, succinic acid, tartaric acid, methanesulfonic acid, or p-toluenesulfonic acid, and which are non toxic to living organisms.

The term “pharmaceutically acceptable salts” denotes salts which are not biologically or otherwise undesirable. Pharmaceutically acceptable salts include both acid and base addition salts.

The term “pharmaceutically acceptable acid addition salt” denotes those pharmaceutically acceptable salts formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, carbonic acid, phosphoric acid, and organic acids selected from aliphatic, cycloaliphatic, aromatic, araliphatic, heterocyclic, carboxylic, and sulfonic classes of organic acids such as formic acid, acetic acid, propionic acid, glycolic acid, gluconic acid, lactic acid, pyruvic acid, oxalic acid, malic acid, maleic acid, maloneic acid, succinic acid, fumaric acid, tartaric acid, citric acid, aspartic acid, ascorbic acid, glutamic acid, anthranilic acid, benzoic acid, cinnamic acid, mandelic acid, embonic acid, phenylacetic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, and salicyclic acid.

The term “pharmaceutically acceptable base addition salt” denotes those pharmaceutically acceptable salts formed with an organic or inorganic base. Examples of acceptable inorganic bases include sodium, potassium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, and aluminum salts. Salts derived from pharmaceutically acceptable organic nontoxic bases includes salts of primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines and basic ion exchange resins, such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, 2-diethylaminoethanol, trimethamine, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, hydrabamine, choline, betaine, ethylenediamine, glucosamine, methylglucamine, theobromine, purines, piperizine, piperidine, N-ethylpiperidine, and polyamine resins.

Stereochemical definitions and conventions used herein generally follow S. P. Parker, Ed., McGraw-Hill Dictionary of Chemical Terms (1984) McGraw-Hill Book Company, New York; and Eliel, E. and Wilen, S., “Stereochemistry of Organic Compounds”, John Wiley & Sons, Inc., New York, 1994. In describing an optically active compound, the prefixes D and L, or R and S, are used to denote the absolute configuration of the molecule about its chiral center(s). The substituents attached to the chiral center under consideration are ranked in accordance with the Sequence Rule of Cahn, Ingold and Prelog. (Cahn et al. Angew. Chem. Inter. Edit. 1966, 5, 385; errata 511). The prefixes D and L or (+) and (−) are employed to designate the sign of rotation of plane-polarized light by the compound, with (−) or L designating that the compound is levorotatory. A compound prefixed with (+) or D is dextrorotatory.

The term “trans-configuration” denotes the configuration within a molecule, wherein a pair of substituents is attached on opposite sides of a stereoisomeric group.

The term “protecting group” denotes the group which selectively blocks a reactive site in a multifunctional compound such that a chemical reaction can be carried out selectively at another unprotected reactive site in the meaning conventionally associated with it in synthetic chemistry. Protecting groups can be removed at the appropriate point. Exemplary protecting groups are amino-protecting groups, carboxy-protecting groups or hydroxy-protecting groups.

The term “amino-protecting group” denotes groups intended to protect an amino group and includes benzyl, benzyloxycarbonyl (carbobenzyloxy, CBZ), Fmoc (9-Fluorenylmethyloxycar-bonyl), p-methoxybenzyloxycarbonyl, p-nitrobenzyloxycarbonyl, tert-butoxycarbonyl (BOC), and trifluoroacetyl. Further examples of these groups are found in T. W. Greene and P. G. M. Wuts, “Protective Groups in Organic Synthesis”, 2nd ed., John Wiley & Sons, Inc., New York, N.Y., 1991, chapter 7; E. Haslam, “Protective Groups in Organic Chemistry”, J. G. W. McOmie, Ed., Plenum Press, New York, N.Y., 1973, Chapter 5, and T. W. Greene, “Protective Groups in Organic Synthesis”, John Wiley and Sons, New York, N.Y., 1981. The term “protected amino group” refers to an amino group substituted by an amino-protecting group.

The term “halo”, “halogen”, and “halide” are used interchangeably herein and denote fluoro, chloro, bromo, or iodo. Particular halogens are fluoro and chloro.

The term “alkyl” denotes a monovalent linear or branched saturated hydrocarbon group of 1 to 12 carbon atoms, in particular of 1 to 7 carbon atoms, more particularly of 1 to 4 carbon atoms, for example, methyl, ethyl, propyl, isopropyl, n-butyl, iso-butyl, sec-butyl, or tert-butyl. Particular alkyl groups are methyl, ethyl, n-propyl, isopropyl, and isobutyl.

The term “alkoxy” denotes a group of the formula —O—R′, wherein R′ is an alkyl group as defined herein. Examples of alkoxy moieties include methoxy, ethoxy, isopropoxy, and tert-butoxy. Particular alkoxy is methoxy.

The term “haloalkyl” denotes an alkyl group as defined herein wherein at least one of the hydrogen atoms has been replaced by the same or different halogen atoms, particularly fluoro atoms. Examples of haloalkyl include monofluoro-, difluoro- or trifluoro-methyl, -ethyl or -propyl, for example 3,3,3-trifluoropropyl, 2-fluoroethyl, 2,2,2-trifluoroethyl, fluoromethyl, or trifluoromethyl. The term “perhaloalkyl” denotes an alkyl group where all hydrogen atoms of the alkyl group have been replaced by the same or different halogen atoms. Particular haloalkyl is trifluoromethyl.

The term “hydroxyalkyl” denotes an alkyl group as defined herein wherein at least one of the hydrogen atoms has been replaced by a hydroxy-group. Particular hydroxyalkyl is hydroxymethyl. The term “haloalkoxy” denotes an alkoxy group wherein at least one of the hydrogen atoms of the alkyl chain has been replaced by the same or different halogen atoms, particularly fluoro atoms. Examples of haloalkoxy include monofluoro-, difluoro- or trifluoro-methoxy, -ethoxy or -propoxy, for example 3,3,3-trifluoropropoxy, 2-fluoroethoxy, 2,2,2-trifluoroethoxy, fluoromethoxy, or trifluoromethoxy. The term “perhaloalkoxy” denotes an alkoxy group where all hydrogen atoms have been replaced by the same or different halogen atoms.

The term “cycloalkyl” denotes a monovalent saturated monocyclic or bicyclic hydrocarbon group of 3 to 10 ring carbon atoms, particularly a monovalent saturated monocyclic hydrocarbon group of 3 to 8 ring carbon atoms. Bicyclic means consisting of two saturated carbocycles having one or more carbon atoms in common. Particular cycloalkyl groups are monocyclic. Examples for monocyclic cycloalkyl are cyclopropyl, cyclobutanyl, cyclopentyl, cyclohexyl or cycloheptyl. Examples for bicyclic cycloalkyl are bicyclo[2.2.1]heptanyl, or bicyclo[2.2.2]octanyl. Particular cycloalkyl is cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. Most particular cycloalkyl is cyclopentyl and cyclohexyl.

The term “cycloalkylalkyl” denotes an alkyl group wherein at least one of the hydrogen atoms is replaced by a cycloalkyl group. Examples of cycloalkylalkyl include cyclopropylmethyl, cyclopropylethyl, cyclobutylpropyl and cyclopentylbutyl.

The term “heterocycloalkyl” denotes a monovalent saturated or partly unsaturated mono- or bicyclic ring system of 4 to 9 ring atoms, containing 1, 2, or 3 ring heteroatoms selected from N, O and S, the remaining ring atoms being carbon. Bicyclic means consisting of two rings having two ring atoms in common, i.e. the bridge separating the two rings is either a single bond or a chain of one or two ring atoms. Examples for monocyclic saturated heterocycloalkyl are azetidinyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydro-thienyl, pyrazolidinyl, imidazolidinyl, oxazolidinyl, isoxazolidinyl, thiazolidinyl, piperidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, piperazinyl, morpholinyl, thiomorpholinyl, 1,1-dioxo-thiomorpholin-4-yl, azepanyl, diazepanyl, homopiperazinyl, or oxazepanyl. Examples for bicyclic saturated heterocycloalkyl are 8-aza-bicyclo[3.2.1]octyl, quinuclidinyl, 8-oxa-3-aza-bicyclo[3.2.1]octyl, 9-aza-bicyclo[3.3.1]nonyl, 3-oxa-9-aza-bicyclo[3.3.1]nonyl, or 3-thia-9-aza-bicyclo[3.3.1]nonyl. Examples for partly unsaturated heterocycloalkyl are dihydrofuryl, imidazolinyl, dihydro-oxazolyl, tetrahydro-pyridinyl, or dihydropyranyl. Particular heterocycloalkyl is oxetanyl, tetrahydrofuranyl, 1,1-dioxo-tetrahydro-1,6-thiophenyl, tetrahydropyranyl, piperazinyl, piperidinyl, morpholinyl and dioxanyl. Most particular heterocycloalkyl is tetrahydropyranyl and dioxanyl.

The term “aromatic” denotes the conventional idea of aromaticity as defined in the literature, in particular in IUPAC—Compendium of Chemical Terminology, 2nd, A. D. McNaught & A. Wilkinson (Eds). Blackwell Scientific Publications, Oxford (1997).

The term “aryl” denotes a monovalent aromatic carbocyclic mono- or bicyclic ring system containing 6 to 10 carbon ring atoms. Examples of aryl moieties include phenyl and naphthyl. Particular aryl is phenyl.

The term “heteroaryl” denotes a monovalent aromatic heterocyclic mono- or bicyclic ring system of 5 to 12 ring atoms, containing 1, 2, 3 or 4 heteroatoms selected from N, O and S, the remaining ring atoms being carbon. Examples of heteroaryl moieties include pyrrolyl, furanyl, thienyl, imidazolyl, oxazolyl, thiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl, pyridinyl, pyrazinyl, pyrazolyl, pyridazinyl, pyrimidinyl, triazinyl, azepinyl, diazepinyl, isoxazolyl, benzofuranyl, isothiazolyl, benzothienyl, indolyl, isoindolyl, isobenzofuranyl, benzimidazolyl, benzoxazolyl, benzoisoxazolyl, benzothiazolyl, benzoisothiazolyl, benzooxadiazolyl, benzothiadiazolyl, benzotriazolyl, purinyl, quinolinyl, isoquinolinyl, quinazolinyl, or quinoxalinyl. Particular heteroaryl groups are isoxalyl, imidazolyl, pyridinyl, 2,3-dihydro-indolyl, benzo[1,3]dioxolyl, quinolinyl, chromanyl, and 2,3-dihydro-benzo[1,4]dioxinyl. Most particular heteroaryl groups are isoxalyl, benzo[1,3]dioxolyl, quinolinyl, chromanyl, are 2,3-dihydro-benzo[1,4]dioxinyl.

The term “oxo” denotes a divalent oxygen atom ═O.

The term “pharmaceutically acceptable” denotes an attribute of a material which is useful in preparing a pharmaceutical composition that is generally safe, non-toxic, and neither biologically nor otherwise undesirable and is acceptable for veterinary as well as human pharmaceutical use.

The term “pharmaceutically acceptable excipient” denotes any ingredient having no therapeutic activity and being non-toxic such as disintegrators, binders, fillers, solvents, buffers, tonicity agents, stabilizers, antioxidants, surfactants or lubricants used in formulating pharmaceutical products.

The term “pharmaceutical composition” (or “composition”) denotes a mixture or solution containing a therapeutically effective amount of an active pharmaceutical ingredient together with pharmaceutically acceptable excipients to be administered to a mammal, e.g., a human, in need thereof.

The term “half maximal inhibitory concentration” (IC50) denotes the concentration of a particular compound required for obtaining 50% inhibition of a biological process in vitro. IC50 values can be converted logarithmically to pIC50 values (−log IC50), in which higher values indicate exponentially greater potency. The IC50 value is not an absolute value but depends on experimental conditions e.g. concentrations employed. The IC50 value can be converted to an absolute inhibition constant (Ki) using the Cheng-Prusoff equation (Biochem. Pharmacol. (1973) 22:3099).

The term “dissociation constant” (Kd) denotes the propensity of a complex (e.g. between a ligand and a receptor) to dissociate reversibly under equilibrium conditions. The term “inhibition constant” (Ki) denotes the absolute binding affinity of a particular inhibitor to a receptor. It is measured using competition binding assays and is equal to the concentration where the particular inhibitor would occupy 50% of the receptors if no competing ligand (e.g. a radioligand) was present. Ki values can be converted logarithmically to pKi values (−log Ki), in which higher values indicate exponentially greater potency.

In detail, the present invention provides compounds of formula (I)

wherein n is 0, 1, 2 or 3;

Y is —C(O)— or —S(O)₂—;

R¹ is hydrogen, halogen, cyano, alkyl, haloalkyl, hydroxy, alkoxy, haloalkoxy, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, —NR⁷R⁸, —C(O)—NR⁷R⁸, or —S(O)₂—R⁷; wherein alkyl, haloalkyl, and alkoxy are each optionally substituted by one, two or three independent R⁵; and wherein cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are each optionally substituted by one, two or three independent R⁶; R², R³ and R⁴ are each independently hydrogen, halogen, alkyl, haloalkyl, hydroxy, alkoxy or haloalkoxy; R⁵ is cyano, hydroxy, alkoxy, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, wherein cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are each optionally substituted by one, two or three independent R⁶; R⁶ is halogen, cyano, alkyl, haloalkyl, hydroxyalkyl, hydroxy, alkoxy, haloalkoxy, oxo, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; R⁷ and R⁸ are each independently hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl, aryl, aryl substituted by halogen, or heteroaryl; and pharmaceutically acceptable salts and esters thereof; and deuterated analogs thereof.

Particular embodiments of present invention are compounds of formula (I) and pharmaceutically acceptable salts thereof and pharmaceutically acceptable esters thereof and deuterated analogs thereof.

Further, it is to be understood that every embodiment relating to a specific residue n, Y, R¹, R², R³, R⁴, R⁵, R⁶, R⁷ or R⁸ as disclosed herein can be combined with any other embodiment relating to another residue n, Y, R¹, R², R³, R⁴, R⁵, R⁶, R⁷ or R⁸ as disclosed herein.

In one embodiment, the present invention provides compounds of formula (I) wherein

n is 0, 1, 2 or 3;

Y is —C(O)— or —S(O)₂—;

R¹ is hydrogen, cyano, alkyl, haloalkyl, hydroxy, alkoxy, haloalkoxy, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, —NR⁷R⁸, —C(O)—NR⁷R⁸, or —S(O)₂—R⁷; wherein alkyl, haloalkyl, and alkoxy are each optionally substituted by one, two or three independent R⁵; and wherein cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are each optionally substituted by one, two or three independent R⁶; R², R³ and R⁴ are each independently hydrogen, halogen, alkyl, haloalkyl, hydroxy, alkoxy or haloalkoxy; R⁵ is cyano, hydroxy, alkoxy, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, wherein cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are each optionally substituted by one, two or three independent R⁶; R⁶ is halogen, cyano, alkyl, haloalkyl, hydroxy, alkoxy, haloalkoxy, oxo, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; R⁷ and R⁸ are each independently hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl, aryl, or heteroaryl; and pharmaceutically acceptable salts and esters thereof.

In one embodiment, the present invention provides compounds of formula (Ia)

wherein n, Y, R¹, R², R³, R⁴, R⁵, R⁶, R⁷ and R⁸ are as defined herein; and pharmaceutically acceptable salts and esters thereof.

In one embodiment, the present invention provides compounds of formula (I) wherein

n is 0, 1, 2 or 3;

Y is —C(O)— or —S(O)₂—;

R¹ is hydrogen, cyano, alkyl, haloalkyl, hydroxy, alkoxy, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein alkyl is optionally substituted by one, two or three independent R⁵; and wherein cycloalkyl, and heteroaryl are each optionally substituted by one, two or three independent R⁶; R², R³ and R⁴ are each independently hydrogen; R⁵ is hydroxy, or alkoxy; R⁶ is halogen, alkyl, hydroxy, or alkoxy; and pharmaceutically acceptable salts and esters thereof.

A particular embodiment of the present invention provides compounds of formula (I) wherein the two opposing substituents at the central cyclohexyl moiety of the molecular backbone, the amidyl residue and the piperazinyl-ethyl residue, are oriented in trans-configuration.

A particular embodiment of the present invention provides compounds of formula (I′)

wherein n, R¹, R², R³ and R⁴ are as defined herein.

A particular embodiment of the present invention provides compounds of formula (I″)

wherein n, R¹, R², R³ and R⁴ are as defined herein.

In a particular embodiment of the invention, n is 0.

In a particular embodiment of the invention, n is 1.

In a particular embodiment of the invention, n is 2.

In a particular embodiment of the invention, n is 3.

In a particular embodiment of the invention, Y is —C(O)—.

In a particular embodiment of the invention, Y is —S(O)₂—.

In a particular embodiment of the invention, R¹ is hydrogen, halogen, cyano, alkyl, haloalkyl, hydroxy, alkoxy, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, —NR⁷R⁸, or —S(O)₂—R⁷; wherein alkyl is optionally substituted by one, two or three independent R⁵; and wherein cycloalkyl, heterocycloalkyl, aryl and heteroaryl are each optionally substituted by one, two or three independent R⁶; and wherein R⁵, R⁶, R⁷ and R⁸ are as described herein.

In a particular embodiment of the invention, R¹ is hydrogen, cyano, alkyl, haloalkyl, hydroxy, alkoxy, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein alkyl is optionally substituted by one, two or three independent R⁵; and wherein cycloalkyl, and heteroaryl are each optionally substituted by one, two or three independent R⁶.

In a particular embodiment of the invention, R¹ is cyano, alkyl, hydroxy, alkoxy, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein alkyl is optionally substituted by one hydroxy or alkoxy; wherein cycloalkyl is optionally substituted by one hydroxy; and wherein heteroaryl is optionally substituted by one alkyl.

In a particular embodiment of the invention, R¹ is hydrogen, fluoro, cyano, ethyl, hydroxy-ethyl, methoxy-ethyl, hydroxy-n-propyl, isopropyl, hydroxy-isopropyl, methoxy-isopropyl, hydroxyl-isobutyl, methoxy-isobutyl, trifluoromethyl, hydroxy, methoxy, cyclopropyl, difluoro-cyclopropyl, hydroxy-cyclopropyl, methoxy-cyclopropyl, cyclobutyl, chloro-cyclobutyl, hydroxy-cyclobutyl, hydroxymethyl-cyclobutyl, cyclopentyl, hydroxy-cyclopentyl, methoxy-cyclopentyl, cyclohexyl, hydroxy-cyclohexyl, methoxy-cyclohexyl, oxetanyl, methyl-oxetanyl, tetrahydrofuranyl, tetrahydro-1,6-thiophenyl, 1,1-dioxo-tetrahydro-1,6-thiophenyl, tetrahydropyranyl, piperazinyl, methyl-piperazinyl, piperidinyl, methyl-piperidinyl, morpholinyl, dioxanyl, phenyl, fluoro-phenyl, cyano-phenyl, morpholinyl-phenyl, isoxazolyl, methyl-isoxazolyl, imidazolyl, methyl-imidazolyl, pyridinyl, 2,3-dihydro-indolyl, benzo[1,3]dioxolyl, quinolinyl, chromanyl, 2,3-dihydro-benzo[1,4]dioxinyl, chlorophenylamine, dimethylamine, or methylsulfonyl.

In a particular embodiment of the invention, R¹ is hydrogen, cyano, ethyl methoxy-ethyl, isopropyl, hydroxy-isopropyl, trifluoromethyl, hydroxy, methoxy, cyclopropyl, difluoro-cyclopropyl, hydroxy-cyclopropyl, cyclobutyl, hydroxy-cyclobutyl, cyclopentyl, methoxy-cyclopentyl, cyclohexyl, hydroxy-cyclohexyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, dioxanyl, phenyl, isoxazolyl, or methyl-isoxazolyl.

In a particular embodiment of the invention, R¹ is cyano, methoxy-ethyl, hydroxy-isopropyl, hydroxy, methoxy, hydroxy-cyclopentyl, hydroxy-cyclohexyl, methoxy-cyclopentyl, tetrahydropyranyl, dioxanyl, phenyl, methyl-isoxazolyl, benzo[1,3]dioxolyl, quinolinyl, chromanyl, or 2,3-dihydro-benzo[1,4]dioxinyl.

In a particular embodiment of the invention, R¹ is cyano, methoxy-ethyl, hydroxy-isopropyl, hydroxy, methoxy, hydroxy-cyclohexyl, tetrahydropyranyl, dioxanyl, phenyl, or methyl-isoxazolyl.

In a particular embodiment of the invention, R², R³ and R⁴ are hydrogen.

In a particular embodiment of the invention, R² is hydrogen.

In a particular embodiment of the invention, R³ is hydrogen.

In a particular embodiment of the invention, R⁴ is hydrogen.

In a particular embodiment of the invention, R⁵ is hydroxy or alkoxy.

In a particular embodiment of the invention, R⁵ is hydroxy or methoxy.

In a particular embodiment of the invention, R⁶ is halogen, cyano, alkyl, hydroxyalkyl, hydroxy, or alkoxy, oxo or heterocycloalkyl.

In a particular embodiment of the invention, R⁶ is halogen, alkyl, hydroxy, or alkoxy.

In a particular embodiment of the invention, R⁶ is fluoro, chloro, cyano, methyl, hydroxymethyl, hydroxy, or methoxy, oxo or morpholinyl.

In a particular embodiment of the invention, R⁶ is fluoro, methyl, hydroxy, or methoxy.

In a particular embodiment of the invention, R⁶ is methyl or hydroxy.

In a particular embodiment of the invention, R⁷ and R⁸ are each independently selected from hydrogen, alkyl, and aryl substituted by halogen.

In a particular embodiment of the invention, R⁷ and R⁸ are each independently selected from hydrogen, methyl, and chlorophenyl.

A particular embodiment of the present invention provides compounds of formula (I) as described in the examples as individual compounds as well as pharmaceutically acceptable salts as well as pharmaceutically acceptable esters thereof. Furthermore, the substituents as found in the specific examples described below individually constitute separate particular embodiments of the present invention.

Particular compounds of formula (I) of present invention are those selected from the group consisting of:

-   Trans-N-{4-[2-(4-Benzo[1,3]dioxol-4-yl-piperazin-1-yl)-ethyl]-cyclohexyl}-acetamide; -   Trans-N-{4-[2-(4-Benzo[1,3]dioxol-4-yl-piperazin-1-yl)-ethyl]-cyclohexyl}-3-methoxy-propionamide; -   Trans-N-{4-[2-(4-Benzo[1,3]dioxol-4-yl-piperazin-1-yl)-ethyl]-cyclohexyl}-2-[1,4]dioxan-2-yl-acetamide; -   Trans-N-{4-[2-(4-Benzo[1,3]dioxol-4-yl-piperazin-1-yl)-ethyl]-cyclohexyl}-2-(S)-[1,4]dioxan-2-yl-acetamide; -   Trans-N-{4-[2-(4-Benzo[1,3]dioxol-4-yl-piperazin-1-yl)-ethyl]-cyclohexyl}-2-(R)-[1,4]dioxan-2-yl-acetamide; -   Trans-N-{4-[2-(4-Benzo[1,3]dioxol-4-yl-piperazin-1-yl)-ethyl]-cyclohexyl}-2-(tetrahydro-furan-2-yl)-acetamide; -   Trans-N-{4-[2-(4-Benzo[1,3]dioxol-4-yl-piperazin-1-yl)-ethyl]-cyclohexyl}-propionamide; -   Trans-N-{4-[2-(4-Benzo[1,3]dioxol-4-yl-piperazin-1-yl)-ethyl]-cyclohexyl}-2-cyclopropyl-acetamide; -   Trans-N-{4-[2-(4-Benzo[1,3]dioxol-4-yl-piperazin-1-yl)-ethyl]-cyclohexyl}-2-methoxy-acetamide; -   Trans-N-{4-[2-(4-Benzo[1,3]dioxol-4-yl-piperazin-1-yl)-ethyl]-cyclohexyl}-2-hydroxy-acetamide; -   Trans-N-{4-[2-(4-Benzo[1,3]dioxol-4-yl-piperazin-1-yl)-ethyl]-cyclohexyl}-benzamide; -   Trans-{4-[2-(4-Benzo[1,3]dioxol-4-yl-piperazin-1-yl)-ethyl]-cyclohexyl}-carbamic     acid methyl ester; -   Trans-N-{4-[2-(4-Benzo[1,3]dioxol-4-yl-piperazin-1-yl)-ethyl]-cyclohexyl}-2-(3-methyl-isoxazol-5-yl)-acetamide; -   Trans-N-{4-[2-(4-Benzo[1,3]dioxol-4-yl-piperazin-1-yl)-ethyl]-cyclohexyl}-2-cyano-acetamide; -   Trans-N-{4-[2-(4-Benzo[1,3]dioxol-4-yl-piperazin-1-yl)-ethyl]-cyclohexyl}-2-(1-hydroxy-cyclohexyl)-acetamide; -   Trans-N-{4-[2-(4-Benzo[1,3]dioxol-4-yl-piperazin-1-yl)-ethyl]-cyclohexyl}-3,3,3-trifluoro-propionamide; -   Trans-N-{4-[2-(4-Benzo[1,3]dioxol-4-yl-piperazin-1-yl)-ethyl]-cyclohexyl}-isobutyramide; -   Trans-N-{4-[2-(4-Benzo[1,3]dioxol-4-yl-piperazin-1-yl)-ethyl]-cyclohexyl}-3-methyl-butyramide; -   Trans-N-{4-[2-(4-Benzo[1,3]dioxol-4-yl-piperazin-1-yl)-ethyl]-cyclohexyl}-butyramide; -   Trans-2,2-Difluoro-cyclopropanecarboxylic acid     {4-[2-(4-benzo[1,3]dioxol-4-yl-piperazin-1-yl)-ethyl]-cyclohexyl}-amide; -   Trans-N-{4-[2-(4-Benzo[1,3]dioxol-4-yl-piperazin-1-yl)-ethyl]-cyclohexyl}-3-methoxy-butyramide; -   Trans-N-{4-[2-(4-Benzo[1,3]dioxol-4-yl-piperazin-1-yl)-ethyl]-cyclohexyl}-2-oxetan-3-yl-acetamide; -   Trans-N-{4-[2-(4-Benzo[1,3]dioxol-4-yl-piperazin-1-yl)-ethyl]-cyclohexyl}-2-((1R,3R)-3-methoxy-cyclopentyl)-acetamide; -   Trans-N-{4-[2-(4-Benzo[1,3]dioxol-4-yl-piperazin-1-yl)-ethyl]-cyclohexyl}-2-hydroxy-2-methyl-propionamide; -   Trans-(S)—N-{4-[2-(4-Benzo[1,3]dioxol-4-yl-piperazin-1-yl)-ethyl]-cyclohexyl}-2-methoxy-propionamide; -   Trans-(R)—N-{4-[2-(4-Benzo[1,3]dioxol-4-yl-piperazin-1-yl)-ethyl]-cyclohexyl}-2-methoxy-propionamide; -   Trans-N-{4-[2-(4-Benzo[1,3]dioxol-4-yl-piperazin-1-yl)-ethyl]-cyclohexyl}-3-hydroxy-3-methyl-butyramide; -   Trans-N-{4-[2-(4-Benzo[1,3]dioxol-4-yl-piperazin-1-yl)-ethyl]-cyclohexyl}-2-(1-hydroxy-cyclobutyl)-acetamide; -   Trans-1-Hydroxy-cyclopropanecarboxylic acid     {4-[2-(4-benzo[1,3]dioxol-4-yl-piperazin-1-yl)-ethyl]-cyclohexyl}-amide; -   Trans-N-{4-[2-(4-Benzo[1,3]dioxol-4-yl-piperazin-1-yl)-ethyl]-cyclohexyl}-2-(S)-tetrahydro-pyran-2-yl-acetamide; -   Trans-N-{4-[2-(4-Benzo[1,3]dioxol-4-yl-piperazin-1-yl)-ethyl]-cyclohexyl}-2-(R)-tetrahydro-pyran-2-yl-acetamide; -   Trans-N-{4-[2-(4-Benzo[1,3]dioxol-4-yl-piperazin-1-yl)-ethyl]-cyclohexyl}-2-(S)-tetrahydro-pyran-3-yl-acetamide; -   Trans-N-{4-[2-(4-Benzo[1,3]dioxol-4-yl-piperazin-1-yl)-ethyl]-cyclohexyl}-2-(R)-tetrahydro-pyran-3-yl-acetamide; -   Trans-N-{4-[2-(4-Benzo[1,3]dioxol-4-yl-piperazin-1-yl)-ethyl]-cyclohexyl}-methanesulfonamide;     and -   pharmaceutically acceptable salts and esters thereof.

Particular compounds of formula (I) of present invention are those selected from the group consisting of:

-   1-Hydroxy-cyclobutanecarboxylic     acid-trans-N-{4-[2-(4-benzo[1,3]dioxol-4-yl-piperazin-1-yl)-ethyl]-cyclohexyl}-amide; -   1-Hydroxy-cyclopentanecarboxylic     acid-trans-N-{4-[2-(4-benzo[1,3]dioxol-4-yl-piperazin-1-yl)-ethyl]-cyclohexyl}-amide; -   1-Hydroxy-cyclohexanecarboxylic acid-trans-N     {4-[2-(4-benzo[1,3]dioxol-4-yl-piperazin-1-yl)-ethyl]-cyclohexyl}-amide; -   Trans-N-{4-[2-(4-Benzo[1,3]dioxol-4-yl-piperazin-1-yl)-ethyl]-cyclohexyl}-2-hydroxy-butyramide; -   (R)-trans-N-{4-[2-(4-Benzo[1,3]dioxol-4-yl-piperazin-1-yl)-ethyl]-cyclohexyl}-2-hydroxy-3-methyl-butyramide; -   (S)-trans-N-{4-[2-(4-Benzo[1,3]dioxol-4-yl-piperazin-1-yl)-ethyl]-cyclohexyl}-2-hydroxy-3-methyl-butyramide; -   1-Methoxy-cyclohexanecarboxylic     acid-trans-N-{4-[2-(4-benzo[1,3]dioxol-4-yl-piperazin-1-yl)-ethyl]-cyclohexyl}-amide; -   (R)-{4-[2-(4-Benzo[1,3]dioxol-4-yl-piperazin-1-yl)-ethyl]-cyclohexyl}-2-hydroxy-propionamide; -   Tetrahydro-pyran-4-carboxylic     acid-trans-N-{4-[2-(4-benzo[1,3]dioxol-4-yl-piperazin-1-yl)-ethyl]-cyclohexyl}-amide; -   Tetrahydro-furan-2-carboxylic     acid-trans-N-{4-[2-(4-benzo[1,3]dioxol-4-yl-piperazin-1-yl)-ethyl]-cyclohexyl}-amide; -   Trans-N-{4-[2-(4-Benzo[1,3]dioxol-4-yl-piperazin-1-yl)-ethyl]-cyclohexyl}-4-morpholin-4-yl-benzamide; -   Trans-N-{4-[2-(4-Benzo[1,3]dioxol-4-yl-piperazin-1-yl)-ethyl]-cyclohexyl}-4-fluoro-benzamide; -   Quinoline-4-carboxylic     acid-trans-N-{4-[2-(4-benzo[1,3]dioxol-4-yl-piperazin-1-yl)-ethyl]-cyclohexyl}-amide; -   Trans-N-{4-[2-(4-Benzo[1,3]dioxol-4-yl-piperazin-1-yl)-ethyl]-cyclohexyl}-nicotinamide; -   2,3-Dihydro-benzo[1,4]dioxine-6-carboxylic     acid-trans-N-{4-[2-(4-benzo[1,3]dioxol-4-yl-piperazin-1-yl)-ethyl]-cyclohexyl}-amide; -   Chroman-3-carboxylic     acid-trans-N-{4-[2-(4-benzo[1,3]dioxol-4-yl-piperazin-1-yl)-ethyl]-cyclohexyl}-amide; -   2-Benzo[1,3]dioxol-5-yl-trans-N-{4-[2-(4-benzo[1,3]dioxol-4-yl-piperazin-1-yl)-ethyl]-cyclohexyl}-acetamide; -   1,1-Dioxo-tetrahydro-1,6-thiophene-3-carboxylic     acid-trans-N-{4-[2-(4-benzo[1,3]dioxol-4-yl-piperazin-1-yl)-ethyl]-cyclohexyl}-amide; -   N-trans-{4-[2-(4-Benzo[1,3]dioxol-4-yl-piperazin-1-yl)-ethyl]-cyclohexyl}-2-(tetrahydro-pyran-4-yl)-acetamide; -   Cyclobutanecarboxylic     acid-trans-N-{4-[2-(4-benzo[1,3]dioxol-4-yl-piperazin-1-yl)-ethyl]-cyclohexyl}-amide; -   Trans-N-{4-[2-(4-Benzo[1,3]dioxol-4-yl-piperazin-1-yl)-ethyl]-cyclohexyl}-2-methanesulfonyl-acetamide; -   Trans-N-{4-[2-(4-Benzo[1,3]dioxol-4-yl-piperazin-1-yl)-ethyl]-cyclohexyl}-2-(4-methoxy-cyclohexyl)-acetamide; -   1-Methyl-piperidine-4-carboxylic     acid-trans-N-{4-[2-(4-benzo[1,3]dioxol-4-yl-piperazin-1-yl)-ethyl]-cyclohexyl}-amide; -   3-Methyl-oxetane-3-carboxylic     acid-trans-N-{4-[2-(4-benzo[1,3]dioxol-4-yl-piperazin-1-yl)-ethyl]-cyclohexyl}-amide; -   Trans-N-{4-[2-(4-Benzo[1,3]dioxol-4-yl-piperazin-1-yl)-ethyl]-cyclohexyl}-4-cyano-benzamide; -   3-Chloro-cyclobutanecarboxylic     acid-trans-N-{4-[2-(4-benzo[1,3]dioxol-4-yl-piperazin-1-yl)-ethyl]-cyclohexyl}-amide; -   Trans-N-{4-[2-(4-Benzo[1,3]dioxol-4-yl-piperazin-1-yl)-ethyl]-cyclohexyl}-2-(4-methyl-piperazin-1-yl)-acetamide; -   1-Methoxy-cyclopropanecarboxylic     acid-trans-N-{4-[2-(4-benzo[1,3]dioxol-4-yl-piperazin-1-yl)-ethyl]-cyclohexyl}-amide; -   Trans-N-{4-[2-(4-Benzo[1,3]dioxol-4-yl-piperazin-1-yl)-ethyl]-cyclohexyl}-2-methoxy-2-methyl-propionamide; -   R-trans-N-{4-[2-(4-Benzo[1,3]dioxol-4-yl-piperazin-1-yl)-ethyl]-cyclohexyl}-2-methoxy-3-methyl-butyramide; -   (S)-trans-N-{4-[2-(4-Benzo[1,3]dioxol-4-yl-piperazin-1-yl)-ethyl]-cyclohexyl}-2-methoxy-3-methyl-butyramide; -   2,2,2-Trifluoro-ethanesulfonic     acid-trans-N-{4-[2-(4-benzo[1,3]dioxol-4-yl-piperazin-1-yl)-ethyl]-cyclohexyl}-amide; -   N-trans     {4-[2-(4-Benzo[1,3]dioxol-4-yl-piperazin-1-yl)-ethyl]-cyclohexyl}-benzenesulfonamide; -   N-trans-{4-[2-(4-Benzo[1,3]dioxol-4-yl-piperazin-1-yl)-ethyl]-cyclohexyl}-4-fluoro-benzenesulfonamide; -   1-Methyl-1H-imidazole-4-sulfonic     acid-trans-N-{4-[2-(4-benzo[1,3]dioxol-4-yl-piperazin-1-yl)-ethyl]-cyclohexyl}-amide; -   N-trans-{4-[2-(4-Benzo[1,3]dioxol-4-yl-piperazin-1-yl)-ethyl]-cyclohexyl}-2,2,2-trifluoro-acetamide; -   2,3-Dihydro-indole-1-carboxylic     acid-trans-N-{4-[2-(4-benzo[1,3]dioxol-4-yl-piperazin-1-yl)-ethyl]-cyclohexyl}-amide; -   N-trans-3-{4-[2-(4-Benzo[1,3]dioxol-4-yl-piperazin-1-yl)-ethyl]-cyclohexyl}-1,1-dimethyl-urea; -   N-trans-{4-[2-(4-Benzo[1,3]dioxol-4-yl-piperazin-1-yl)-ethyl]-cyclohexyl}-2-fluoro-acetamide; -   N-trans-{4-[2-(4-Benzo[1,3]dioxol-4-yl-piperazin-1-yl)-ethyl]-cyclohexyl}-2-(3-hydroxymethyl-cyclobutyl)-acetamide; -   N-trans-1{4-[2-(4-Benzo[1,3]dioxol-4-yl-piperazin-1-yl)-ethyl]-cyclohexyl}-3-(4-chloro-phenyl)-urea; -   N-trans-{4-[2-(4-benzo[1,3]dioxol-4-yl-piperazin-1-yl)-ethyl]-cyclohexyl}-N,N-dimethyl-sulfamide; -   Morpholine-4-sulfonic     acid-trans-N-{4-[2-(4-benzo[1,3]dioxol-4-yl-piperazin-1-yl)-ethyl]-cyclohexyl}-amide; -   Trans-N-{4-[2-(4-Benzo(2,2-D2)-[1,3]dioxol-4-yl-piperazin-1-yl)-ethyl]-cyclohexyl}-2-(S)-[1,4]dioxan-2-yl-acetamide; -   N-trans     {4-[2-(4-Benzo(2,2-D2)[1,3]dioxol-4-yl-piperazin-1-yl)-ethyl]-cyclohexyl}-2-methoxy-acetamide; -   N-trans {4-[2-(4-Benzo(2,2-D2)     [1,3]dioxol-4-yl-piperazin-1-yl)-ethyl]-cyclohexyl}-isobutyramide; -   N-trans     {4-[2-(4-Benzo(2,2-D2)-[1,3]dioxol-4-yl-piperazin-1-yl)-ethyl]-cyclohexyl}-2-hydroxy-2-methyl-propionamide; -   R—N-trans     {4-[2-(4-Benzo(2,2-D2)-[1,3]dioxol-4-yl-piperazin-1-yl)-ethyl]-cyclohexyl}-2-methoxypropanamide;     and -   pharmaceutically acceptable salts and esters thereof.

Particular compounds of formula (I) of present invention are those selected from the group consisting of:

-   Trans-N-{4-[2-(4-Benzo[1,3]dioxol-4-yl-piperazin-1-yl)-ethyl]-cyclohexyl}-2-[1,4]dioxan-2-yl-acetamide; -   Trans-N-{4-[2-(4-Benzo[1,3]dioxol-4-yl-piperazin-1-yl)-ethyl]-cyclohexyl}-2-(S)-[1,4]dioxan-2-yl-acetamide; -   Trans-N-{4-[2-(4-Benzo[1,3]dioxol-4-yl-piperazin-1-yl)-ethyl]-cyclohexyl}-2-methoxy-acetamide; -   Trans-N-{4-[2-(4-Benzo[1,3]dioxol-4-yl-piperazin-1-yl)-ethyl]-cyclohexyl}-2-hydroxy-acetamide; -   Trans-N-{4-[2-(4-Benzo[1,3]dioxol-4-yl-piperazin-1-yl)-ethyl]-cyclohexyl}-benzamide; -   Trans-N-{4-[2-(4-Benzo[1,3]dioxol-4-yl-piperazin-1-yl)-ethyl]-cyclohexyl}-2-(3-methyl-isoxazol-5-yl)-acetamide; -   Trans-N-{4-[2-(4-Benzo[1,3]dioxol-4-yl-piperazin-1-yl)-ethyl]-cyclohexyl}-2-(1-hydroxy-cyclohexyl)-acetamide; -   Trans-N-{4-[2-(4-Benzo[1,3]dioxol-4-yl-piperazin-1-yl)-ethyl]-cyclohexyl}-2-hydroxy-2-methyl-propionamide; -   Trans-(R)—N-{4-[2-(4-Benzo[1,3]dioxol-4-yl-piperazin-1-yl)-ethyl]-cyclohexyl}-2-methoxy-propionamide; -   Trans-N-{4-[2-(4-Benzo[1,3]dioxol-4-yl-piperazin-1-yl)-ethyl]-cyclohexyl}-2-(R)-tetrahydro-pyran-2-yl-acetamide; -   Trans-N-{4-[2-(4-Benzo[1,3]dioxol-4-yl-piperazin-1-yl)-ethyl]-cyclohexyl}-methanesulfonamide; -   1-Hydroxy-cyclopentanecarboxylic     acid-trans-N-{4-[2-(4-benzo[1,3]dioxol-4-yl-piperazin-1-yl)-ethyl]-cyclohexyl}-amide; -   1-Hydroxy-cyclohexanecarboxylic acid-trans-N     {4-[2-(4-benzo[1,3]dioxol-4-yl-piperazin-1-yl)-ethyl]-cyclohexyl}-amide; -   Tetrahydro-pyran-4-carboxylic     acid-trans-N-{4-[2-(4-benzo[1,3]dioxol-4-yl-piperazin-1-yl)-ethyl]-cyclohexyl}-amide; -   Quinoline-4-carboxylic     acid-trans-N-{4-[2-(4-benzo[1,3]dioxol-4-yl-piperazin-1-yl)-ethyl]-cyclohexyl}-amide; -   2,3-Dihydro-benzo[1,4]dioxine-6-carboxylic     acid-trans-N-{4-[2-(4-benzo[1,3]dioxol-4-yl-piperazin-1-yl)-ethyl]-cyclohexyl}-amide; -   Chroman-3-carboxylic     acid-trans-N-{4-[2-(4-benzo[1,3]dioxol-4-yl-piperazin-1-yl)-ethyl]-cyclohexyl}-amide; -   2-Benzo[1,3]dioxol-5-yl-trans-N-{4-[2-(4-benzo[1,3]dioxol-4-yl-piperazin-1-yl)-ethyl]-cyclohexyl}-acetamide; -   Trans-N-{4-[2-(4-Benzo[1,3]dioxol-4-yl-piperazin-1-yl)-ethyl]-cyclohexyl}-2-(4-methoxy-cyclohexyl)-acetamide; -   Trans-N-{4-[2-(4-Benzo(2,2-D2)-[1,3]dioxol-4-yl-piperazin-1-yl)-ethyl]-cyclohexyl}-2-(S)-[1,4]dioxan-2-yl-acetamide; -   N-trans     {4-[2-(4-Benzo(2,2-D2)-[1,3]dioxol-4-yl-piperazin-1-yl)-ethyl]-cyclohexyl}-2-hydroxy-2-methyl-propionamide;     and -   pharmaceutically acceptable salts and esters thereof.

Particular compounds of formula (I) of present invention are those selected from the group consisting of:

-   Trans-N-{4-[2-(4-Benzo[1,3]dioxol-4-yl-piperazin-1-yl)-ethyl]-cyclohexyl}-2-hydroxy-2-methyl-propionamide; -   N-trans     {4-[2-(4-Benzo(2,2-D2)-[1,3]dioxol-4-yl-piperazin-1-yl)-ethyl]-cyclohexyl}-2-hydroxy-2-methyl-propionamide;     and -   pharmaceutically acceptable salts and esters thereof.

The invention further provides a process for the manufacture of compounds of formula (I) as defined above which comprises:

a) the reaction of a compound of formula (V)

with a compound of formula R¹(CH₂)_(n)C(O)OH, R¹(CH₂)_(n)C(O)OR or R¹(CH₂)_(n)S(O)₂Cl, wherein n, R¹, R², R³ and R⁴ are as defined above and R is alkyl; or b) the reaction of a compound of formula (II)

with a compound of formula (VI)

wherein n, Y, R¹, R², R³ and R⁴ are as defined above.

Particularly, compounds of formula (I) can be prepared following standard methods in accordance with Schemes 1 or 2.

According to Scheme 1, in a first step, a compound of formula (II) is reacted with an aldehyde of formula (III) under reductive amination conditions such as for example the use of sodium triacetoxyborohydride (Na(AcO)₃BH) in a solvent such as 1,2-dichloroethane in the presence of methanol (MeOH) or an acid such as acetic acid (AcOH) to give a compound of formula (IV). The amino moiety of aldehyde (III) is protected with an amino-protecting group such as a Boc moiety. In a second step, compounds of formula (IV) are deprotected to give compounds of formula (V). In such cases where the amino-protecting group is a Boc functionality, compounds of formula (IV) can be reacted with an acid as for example HCl in an appropriate solvent mixture such as ethylacetate (AcOEt) and MeOH to give primary amines isolated as the HCl salts (V).

Compounds of formula (V) can be reacted in a third step with a number of different nucleophiles to obtain compounds of formula (I). For instance reaction of compounds of formula (V) with a carboxylic acid of general structure R¹(CH₂)_(n)C(O)OH in the presence of a coupling agent such as O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate (TBTU) and a base such as Hunig's base (N,N-Diisopropylethylamine, DIPEA) in a solvent such as dimethylformamide (DMF) leads to compounds of formula (I′). In some instances carboxylic acids of general structure R¹(CH₂)_(n)C(O)OH or their salts can be prepared by saponification of an ester of formula R¹(CH₂)_(n)C(O)OR, wherein R is alkyl, with a reagent such as a base like LiOH or mild reagents like potassium trimethylsilanolate (KOSiMe₃) in a solvent such as dichloromethane (DCM) followed by full evaporation of all solvent and direct use of the crude in the amide coupling step described above to obtain compounds of formula (I′).

Yet in another instance, compounds of formula (V) can be reacted with an appropriate reagent of general structure R¹(CH₂)_(n)S(O)₂Cl in the presence of a base such as triethylamine (Et₃N) in a solvent such as DCM to obtain compounds of formula (I″).

Derivatization at the primary amine does not necessarily need to be carried out in a last step, but can occur already prior to the reductive amination step, thus avoiding the use of an amino-protecting group. According to Scheme 2, the reductive amination of a compound of formula (II) with an aldehyde of formula (VI) under conditions well known to the person skilled in the art, will directly lead to an amide of formula (I). An example for appropriate conditions for this step is the use of Na(AcO)₃BH in a solvent such as 1,2-dichloroethane in the presence or not of MeOH or an acid such as AcOH. Methods to generate compounds of formula (VI) have been described (e.g. WO 2007/093540).

In some occasions the starting material (II) might need to be synthesized as it is not commercially available. For the preparation of deuterated material, treatment of the diol with the corresponding D2-dibromomethane is needed. According to Scheme 3, compounds of formula (II) can be obtained from compounds of formula (VII), wherein X is halogen, particularly bromo, for example, by coupling with a compound of formula (VIII), wherein Z is an amino-protecting group, particularly Boc. The coupling between the compound of formula (VII) and the compound of formula (VIII) is performed under conditions well known to the person skilled in the art to obtain a compound of formula (IX). For instance under Buchwald-Hartwig conditions using a catalyst such as Palladium (II) Acetate in presence of a ligand, particularly racemic-2,2′-bis(diphenylphosphino)-1,1′-binaphtyl, in the presence of a base, particularly Cesium carbonate, in a solvent, particularly Toluene. Alternatively, 2-(di-tert-butylphosphino) biphenyl can be employed as ligand and sodium tert-butoxide employed as the base. Other coupling conditions are well known to person skilled in the art. In a second step, compounds of formula (IX), where Z is an amino-protecting group, particularly Boc, can be reacted with an acid, particularly HCl, in an appropriate solvent mixture, particularly dioxane and MeOH, to give primary amines of formula (II), isolated as the HCl salts.

The corresponding salts of compounds of formula (I) with acids can be obtained by standard methods known to the person skilled in the art, e.g. by dissolving the compound of formula (I) in a suitable solvent such as e.g. dioxan or tetrahydrofuran (THF) and adding an appropriate amount of the corresponding acid. The products can usually be isolated by filtration or by chromatography.

The conversion of compounds of formula (I) into pharmaceutically acceptable esters can be carried out e.g. by treatment of a suitable hydroxy-group present in the molecule with a suitable carboxylic acid using e.g. a condensating reagent such as benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (BOP), N,N-dicylohexylcarbodiimide (DCC), N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (EDCI) or O-(1,2-dihydro-2-oxo-1-pyridyl)-N,N,N,N-tetra-methyluronium-tetrafluoroborate (TPTU).

Insofar as their preparation is not described in the examples, the compounds of formula (I) as well as all intermediate products can be prepared according to analogous methods or according to the methods set forth above. Starting materials are commercially available, known in the art or can be prepared by methods known in the art or in analogy thereto.

The present invention also provides compounds of formula (I) as defined above, when prepared by a process as described above.

Another embodiment provides pharmaceutical compositions or medicaments containing the compounds of the invention and a therapeutically inert carrier, diluent or pharmaceutically acceptable excipient, as well as methods of using the compounds of the invention to prepare such compositions and medicaments.

Compositions are formulated, dosed, and administered in a fashion consistent with good medical practice. Factors for consideration in this context include the particular disorder being treated, the particular mammal being treated, the clinical condition of the individual patient, the cause of the disorder, the site of delivery of the agent, the method of administration, the scheduling of administration, and other factors known to medical practitioners.

The compounds of the invention can be administered by any suitable means, including oral, topical (including buccal and sublingual), rectal, vaginal, transdermal, parenteral, subcutaneous, intraperitoneal, intrapulmonary, intradermal, intrathecal and epidural and intranasal, and, if desired for local treatment, intralesional administration. Parenteral infusions include intramuscular, intravenous, intraarterial, intraperitoneal, or subcutaneous administration.

The compounds of the present invention can be administered in any convenient administrative form, e.g., tablets, powders, capsules, solutions, dispersions, suspensions, syrups, sprays, suppositories, gels, emulsions, patches, etc. Such compositions can contain components conventional in pharmaceutical preparations, e.g., diluents, carriers, pH modifiers, preservatives, solubilizers, stabilizers, wetting agents, emulsifiers, sweeteners, colorants, flavorants, salts for varying the osmotic pressure, buffers, masking agents, antioxidants, and further active agents. They can also comprise still other therapeutically valuable substances.

A typical formulation is prepared by mixing a compound of the present invention and a carrier or excipient. Suitable carriers and excipients are well known to those skilled in the art and are described in detail in, e.g., Ansel H. C. et al., Ansel's Pharmaceutical Dosage Forms and Drug Delivery Systems (2004) Lippincott, Williams & Wilkins, Philadelphia; Gennaro A. R. et al., Remington: The Science and Practice of Pharmacy (2000) Lippincott, Williams & Wilkins, Philadelphia; and Rowe R. C, Handbook of Pharmaceutical Excipients (2005) Pharmaceutical Press, Chicago. The formulations can also include one or more buffers, stabilizing agents, surfactants, wetting agents, lubricating agents, emulsifiers, suspending agents, preservatives, antioxidants, opaquing agents, glidants, processing aids, colorants, sweeteners, perfuming agents, flavoring agents, diluents and other known additives to provide an elegant presentation of the drug (i.e., a compound of the present invention or pharmaceutical composition thereof) or aid in the manufacturing of the pharmaceutical product (i.e., medicament).

The dosage at which compounds of the invention can be administered can vary within wide limits and will, of course, be fitted to the individual requirements in each particular case. In general, in the case of oral administration a daily dosage of about 0.1 to 1000 mg per person of a compound of formula (I) should be appropriate, although the above upper limit can also be exceeded when necessary.

An example of a suitable oral dosage form is a tablet containing about 100 mg to 500 mg of the compound of the invention compounded with about 30 to 90 mg anhydrous lactose, about 5 to 40 mg sodium croscarmellose, about 5 to 30 mg polyvinylpyrrolidone (PVP) K30, and about 1 to 10 mg magnesium stearate. The powdered ingredients are first mixed together and then mixed with a solution of the PVP. The resulting composition can be dried, granulated, mixed with the magnesium stearate and compressed to tablet form using conventional equipment.

An example of an aerosol formulation can be prepared by dissolving the compound, for example 10 to 100 mg, of the invention in a suitable buffer solution, e.g. a phosphate buffer, adding a tonicifier, e.g. a salt such as sodium chloride, if desired. The solution can be filtered, e.g., using a 0.2 μm filter, to remove impurities and contaminants.

As described above, the novel compounds of the present invention and their pharmaceutically acceptable salts and esters possess valuable pharmacological properties and are dual modulators of the 5-HT_(2A) and D₃ receptors. The compounds of the present invention can therefore be used, either alone or in combination with other drugs, for the treatment or prevention of diseases which are modulated by ligands of the 5-HT_(2A) or D₃ receptors. These diseases include, but are not limited to psychotic disorders, depression, anxiety, drug addiction, attention deficit hyperactivity disorders, dementia and memory impairment, wherein psychotic disorders include schizophrenia, positive, negative and/or cognitive symptoms associated with schizophrenia, schizoaffective disorders, bipolar disease, mania, psychotic depression, and other psychoses involving paranoia and delusions.

The invention therefore also provides pharmaceutical compositions containing a compound as defined above and a pharmaceutically acceptable excipient.

The invention likewise embraces compounds as described above for use as medicament, especially as medicament for the treatment or prevention of diseases which are related to the 5-HT_(2A) or D₃ receptors, particularly for the treatment or prevention of psychotic disorders, depression, anxiety, drug addiction, attention deficit hyperactivity disorders, dementia and memory impairment, wherein psychotic disorders include schizophrenia, positive, negative and/or cognitive symptoms associated with schizophrenia, schizoaffective disorders, bipolar disease, mania, psychotic depression, and other psychoses involving paranoia and delusions.

In another embodiment, the invention provides a method for the treatment or prevention of diseases which are related to the 5-HT_(2A) or D₃ receptors, particularly for the treatment or prevention of psychotic disorders, depression, anxiety, drug addiction, attention deficit hyperactivity disorders, dementia and memory impairment, wherein psychotic disorders include schizophrenia, positive, negative and/or cognitive symptoms associated with schizophrenia, schizoaffective disorders, bipolar disease, mania, psychotic depression, and other psychoses involving paranoia and delusions, which method comprises administering a compound as defined above to a human being or animal.

The invention also embraces the use of compounds as defined above for the treatment or prevention of diseases which are related to the 5-HT_(2A) or D₃ receptors, particularly for the treatment or prevention of psychotic disorders, depression, anxiety, drug addiction, attention deficit hyperactivity disorders, dementia and memory impairment, wherein psychotic disorders include schizophrenia, positive, negative and/or cognitive symptoms associated with schizophrenia, schizoaffective disorders, bipolar disease, mania, psychotic depression, and other psychoses involving paranoia and delusions.

The invention also provides the use of compounds as described above for the preparation of medicaments for the treatment or prevention of diseases which are related to the 5-HT_(2A) or D₃ receptors, particularly for the treatment or prevention of psychotic disorders, depression, anxiety, drug addiction, attention deficit hyperactivity disorders, dementia and memory impairment, wherein psychotic disorders include schizophrenia, positive, negative and/or cognitive symptoms associated with schizophrenia, schizoaffective disorders, bipolar disease, mania, psychotic depression, and other psychoses involving paranoia and delusions. Such medicaments comprise a compound as described above.

Particularly, compounds of present invention can be used in the treatment or prevention of psychotic disorders including schizophrenia as well as positive, negative and/or cognitive symptoms associated with schizophrenia.

The invention will be more fully understood by reference to the following examples. They should not, however, be construed as limiting the scope of the invention.

Intermediates Intermediate A Trans-4-[2-(4-Benzo[1,3]dioxol-4-yl-piperazin-1-yl)-ethyl]-cyclohexylamine hydrochloride

Step A: Tert-butyl 4-(benzo[d][1,3]dioxol-4-yl)piperazine-1-carboxylate

Tert-butyl piperazine-1-carboxylate (1.11 g, 5.97 mmol) was added to a solution of 4-bromobenzo[d][1,3]dioxole (1 g, 4.97 mmol) in Toluene (15.0 ml). The resulting suspension was degassed using a stream of argon. Cesium carbonate (2.27 g, 558 μl, 6.96 mmol), racemic-2,2′-bis(diphenylphosphino)-1,1′-binaphtyl (232 mg, 373 μmol, Eq: 0.075) and Palladium (II) Acetate (55.8 mg, 249 μmol) were added to this mixture. The reaction was then heated at 100° C. over night. The reaction was cooled to rt, 40 ml of water was added and the mixture was extracted with Ethyl Acetate (2×80 ml). The organic layers were dried over MgSO₄ and concentrated under vacuum. The crude material was purified by flash chromatography (silica gel, 50 g, 0% to 50% EtOAc in heptane). to yield tert-butyl 4-(benzo[d][1,3]dioxol-4-yl)piperazine-1-carboxylate as a white solid (1.15 g, 75%). MS (ISP) m/z=307.4 [(M+H)⁺].

Step B: 1-(benzo[d][1,3]dioxol-4-yl)piperazine hydrochloride

In a 50 mL flask, Tert-butyl 4-(benzo[d][1,3]dioxol-4-yl)piperazine-1-carboxylate (1.145 g, 3.74 mmol) was combined with dichloromethane M (20 ml) to give a colorless solution. Hydrochloric acid solution, 4M in dioxane (9.34 ml, 37.4 mmol) was added and the reaction mixture was stirred for 4 hours at room temperature. 15 ml of Diisoproylether were added and the mixture was stirred for 5 min at 0° C. The precipitate was collected by filtration, washed with 2 ml of diisopropylether and dried to yield the title compound as a white solid (0.955 grs, 100%). MS (ISP) m/z=207.4 [(M+H)⁺].

Step C: Trans-{4-[2-(4-Benzo[1,3]dioxol-4-yl-piperazin-1-yl)-ethyl]-cyclohexyl}-carbamic acid tert-butyl ester

To a stirred solution of 1-(benzo[d][1,3]dioxol-4-yl)piperazine hydrochloride (0.950 g, 3.91 mmol) in dichloromethane (38 ml) and methanol (7.6 ml) was added at room temperature commercially available trans-tert-butyl-4-(2-oxoethyl)-cyclohexylcarbamate (1.23 g, 5.09 mmol) and triethylamine (0.376 g, 0.518 ml, 3.72 mmol) and the solution was allowed to stir for 120 min. Sodium triacetoxyboron hydride (1.49 g, 7.05 mmol) was added portion wise and the mixture was allowed to stir for 16 h at room temperature. The solution was poured into saturated sodium bicarbonate solution (75 ml) and extracted with dichloromethane (2×50 ml). The combined organic layers were dried (MgSO₄) and evaporated. The crude material was purified by flash chromatography on silica gel (dichloromethane/MeOH 0-10%) to yield trans-{4-[2-(4-benzofuran-4-yl-piperidin-1-yl)-ethyl]-cyclohexyl}-carbamic acid tert-butyl ester as a white solid (1.53 g, 91%), MS (ISP) m/z=432.5 [(M+H)⁺].

Step D: Trans-4-[2-(4-Benzo[1,3]dioxol-4-yl-piperazin-1-yl)-ethyl]-cyclohexylamine hydrochloride

To a mixture of trans-{4-[2-(4-benzofuran-4-yl-piperidin-1-yl)-ethyl]-cyclohexyl}-carbamic acid tert-butyl ester (1.53 g, 3.48 mmol) in dichloromethane (20 ml) was added at room temperature hydrochloric acid solution (4M in dioxane, 8.69 ml, 34.8 mmol) and the mixture was allowed to stir for 2 h, the solvent was evaporated, diisopropyl ether (15 ml) were added and the mixture was allowed to stir for 10 min at room temperature. The precipitate was collected by filtration, washed with diisopropyl ether and dried to yield the title compound as a white solid (1.3 g, 100%), MS (ISP) m/z=332.2 [(M+H)⁺].

Intermediate B 4-[2-(4-Benzo(2,2-D2)-[1,3]dioxol-4-yl-piperazin-1-yl)-ethyl]-cyclohexylamine hydrochloride

Step A: 4-bromo(2,2-D2)-1,3-benzodioxole

In a 100 mL round-bottomed flask, 3-bromobenzene-1,2-diol (500 mg, 2.65 mmol, Eq: 1.00) was combined with DMF (10 ml) to give a colorless solution. Dibromomethane-D2 (698 mg, 3.97 mmol, Eq: 1.5) and Cs₂CO₃ (2.15 g, 6.61 mmol, Eq: 2.5) were added. The reaction mixture was stirred for 2 hours at 100° C. The reaction mixture was poured into mL H₂O and extracted with EtOAc (3×50 mL). The organic layers were dried over Na₂SO₄ and concentrated in vacuo. The crude material was purified by flash chromatography (silica gel, 20, 0% to 30% EtOAc in heptane) to obtain 4-bromo(2,2-D2)-1,3-benzodioxole as a colorless liquid (423 mg, 78.8%), MS (GC-EI-MS) m/z=202.0.

Step B: 4-Benzo(2,2-D2)-[1,3]dioxol-4-yl-piperazine-1-carboxylic acid tert-butyl ester

The title compound was prepared using 4-bromo(2,2-D2)-1,3-benzodioxole (200 mg, 0.985 mmol) and tert-butyl piperazine-1-carboxylate in accordance with step A from intermediate A to yield a white solid (244 mg, 80.3%), MS (ISP) m/z=309.1 [(M+H)⁺].

Step C: 1-Benzo(2,2-D2)-[1,3]dioxol-4-yl-piperazine hydrochloride

The title compound was prepared using 4-Benzo(2,2-D2)-[1,3]dioxol-4-yl-piperazine-1-carboxylic acid tert-butyl ester (240 mg, 0.778 mmol) in accordance with step B from intermediate A to yield a white solid (200 mg, 105%), MS (ISP) m/z=209.1 [(M+H)⁺].

Step D: {4-[2-(4-Benzo(2,2-D2)-[1,3]dioxol-4-yl-piperazin-1-yl)-ethyl]-cyclohexyl}-carbamic acid tert-butyl ester

The title compound was prepared using 1-Benzo(2,2-D2)-[1,3]dioxol-4-yl-piperazine hydrochloride (195 mg, 0.797 mmol) and trans-tert-butyl-4-(2-oxoethyl)-cyclohexylcarbamate in accordance with step C from intermediate A to yield a white solid (244 mg, 70.6%), MS (ISP) m/z=434.4 [(M+H)⁺].

Step E: 4-[2-(4-Benzo(2,2-D2)-[1,3]dioxol-4-yl-piperazin-1-yl)-ethyl]-cyclohexylamine hydrochloride

The title compound was prepared using {4-[2-(4-Benzo(2,2-D2)-[1,3]dioxol-4-yl-piperazin-1-yl)-ethyl]-cyclohexyl}-carbamic acid tert-butyl ester (240 mg, 0.554 mmol) in accordance with step B from intermediate A to yield a white solid (238 mg, 116%), MS (ISP) m/z=334.1 [(M+H)⁺].

EXAMPLES Example 1 Trans-N-{4-[2-(4-Benzo[1,3]dioxol-4-yl-piperazin-1-yl)-ethyl]-cyclohexyl}-acetamide

To a stirred mixture of Trans-4-[2-(4-Benzo[1,3]dioxol-4-yl-piperazin-1-yl)-ethyl]-cyclohexylamine trihydrochloride (Intermediate A) (50 mg, 0.136 mmol) in DMF (1 ml) was added N,N-diisopropylethylamine (62 mg, 0.0831 ml, 0.476 mmol), acetic acid (9.8 mg, 9.33 μl, 0.163 mmol) and TBTU (52.4 mg, 0.163 mmol). The mixture was allowed to stir at room temperature for 4 h and poured into ice/water (0.5 ml). The crude reaction mixture was concentrated in vacuo. The reaction mixture was solved with sat NaHCO₃ (1×10 mL). and extracted with dichloromethane (2×20 mL). The organic layers were dried over MgSO₄ and concentrated in vacuo. The crude material was purified by flash chromatography (silica gel, 100 g, 0% to 20% MeOH in dichloromethane) to yield the title compound as an off-white solid (53 mg, 62%), MS (ISP) m/z=374.3 [(M+H)⁺].

Example 2 Trans-N-{4-[2-(4-Benzo[1,3]dioxol-4-yl-piperazin-1-yl)-ethyl]-cyclohexyl}-3-methoxy-propionamide

The title compound, off-white solid (36 mg, 64%), MS (ISP) m/z=418.4 [(M+H)⁺], was prepared in accordance with the general method of example 1 from Trans-4-[2-(4-Benzo[1,3]dioxol-4-yl-piperazin-1-yl)-ethyl]-cyclohexylamine hydrochloride (Intermediate A) (50 mg, 0.136 mmol) and 3-methoxypropionic acid.

Example 3 Trans-N-{4-[2-(4-Benzo[1,3]dioxol-4-yl-piperazin-1-yl)-ethyl]-cyclohexyl}-2-[1,4]dioxan-2-yl-acetamide

The title compound, off-white solid (39 mg, 63%), MS (ISP) m/z=460.5 [(M+H)⁺], was prepared in accordance with the general method of example 1 Trans-4-[2-(4-Benzo[1,3]dioxol-4-yl-piperazin-1-yl)-ethyl]-cyclohexylamine hydrochloride

(intermediate A) (50 mg, 0.136 mmol) and rac-(1,4-dioxan-2-yl)-acetic acid obtained from saponification of the racemic [1,4]Dioxan-2-yl-acetic acid ethyl ester prepared as reported in Tetrahedron Vol. 45, 1989, pp. 69-76.

Example 4 Trans-N-{4-[2-(4-Benzo[1,3]dioxol-4-yl-piperazin-1-yl)-ethyl]-cyclohexyl}-2-(S) or (R)[1,4]dioxan-2-yl-acetamide

The title compound, white solid (10 mg, 41%), MS (ISP) m/z=460.4 [(M+H)⁺], was prepared in accordance with the general method of example 1 from Trans-4-[2-(4-Benzo[1,3]dioxol-4-yl-piperazin-1-yl)-ethyl]-cyclohexylamine hydrochloride (Intermediate A) (20 mg, 0.0543 mmol) and the chiral (S) or (R)-2-(1,4-dioxan-2-yl)acetic acid obtained from chiral separation of rac-[1,4]Dioxan-2-yl-acetic acid benzyl ester (using a Chiralpak AD column with 25% of EtOH in heptane) and hydrogenation to remove the benzyl ester.

Example 5 Trans-N-{4-[2-(4-Benzo[1,3]dioxol-4-yl-piperazin-1-yl)-ethyl]-cyclohexyl}-2-(R) or (S)-[1,4]dioxan-2-yl-acetamide

The title compound, white solid (9 mg, 36%), MS (ISP) m/z=460.5 [(M+H)⁺], was prepared in accordance with the general method of example 1 from Trans-4-[2-(4-Benzo[1,3]dioxol-4-yl-piperazin-1-yl)-ethyl]-cyclohexylamine hydrochloride (Intermediate A) (20 mg, 0.0543 mmol) and the chiral (R)- or (S)-2-(1,4-dioxan-2-yl)acetic acid obtained from chiral separation of rac-[1,4]Dioxan-2-yl-acetic acid benzyl ester (using a Chiralpak AD column with 25% of EtOH in heptane) and hydrogenation to remove the benzyl ester.

Example 6 Trans-N-{4-[2-(4-Benzo[1,3]dioxol-4-yl-piperazin-1-yl)-ethyl]-cyclohexyl}-2-(tetrahydro-furan-2-yl)-acetamide

The title compound, white solid (11 mg, 44%), MS (ISP) m/z=444.4 [(M+H)⁺], was prepared in accordance with the general method of example 1 from Trans-4-[2-(4-Benzo[1,3]dioxol-4-yl-piperazin-1-yl)-ethyl]-cyclohexylamine hydrochloride (Intermediate A) (20 mg, 0.0543 mmol) and 2-(tetrahydrofuran-2-yl)acetic acid.

Example 7 Trans-N-{4-[2-(4-Benzo[1,3]dioxol-4-yl-piperazin-1-yl)-ethyl]-cyclohexyl}-propionamide

The title compound, white solid (10 mg, 48%), MS (ISP) m/z=388.3 [(M+H)⁺], was prepared in accordance with the general method of example 1 from Trans-4-[2-(4-Benzo[1,3]dioxol-4-yl-piperazin-1-yl)-ethyl]-cyclohexylamine hydrochloride (Intermediate A) (20 mg, 0.0543 mmol) and propionic acid.

Example 8 Trans-N-{4-[2-(4-Benzo[1,3]dioxol-4-yl-piperazin-1-yl)-ethyl]-cyclohexyl}-2-cyclopropyl-acetamide

The title compound, white solid (11.5 mg, 51%), MS (ISP) m/z=414.3 [(M+H)⁺], was prepared in accordance with the general method of example 1 from Trans-4-[2-(4-Benzo[1,3]dioxol-4-yl-piperazin-1-yl)-ethyl]-cyclohexylamine hydrochloride (Intermediate A) (20 mg, 0.0543 mmol) and 2-cyclopropylacetic acid.

Example 9 Trans-N-{4-[2-(4-Benzo[1,3]dioxol-4-yl-piperazin-1-yl)-ethyl]-cyclohexyl}-2-methoxy-acetamide

The title compound, white solid (10.3 mg, 47%), MS (ISP) m/z=404.5 [(M+H)⁺], was prepared in accordance with the general method of example 1 from Trans-4-[2-(4-Benzo[1,3]dioxol-4-yl-piperazin-1-yl)-ethyl]-cyclohexylamine hydrochloride (Intermediate A) (20 mg, 0.0543 mmol) and 2-methoxyacetic acid.

Example 10 Trans-N-{4-[2-(4-Benzo[1,3]dioxol-4-yl-piperazin-1-yl)-ethyl]-cyclohexyl}-2-hydroxy-acetamide

The title compound, white solid (11 mg, 50%), MS (ISP) m/z=390.3 [(M+H)⁺], was prepared in accordance with the general method of example 1 from Trans-4-[2-(4-Benzo[1,3]dioxol-4-yl-piperazin-1-yl)-ethyl]-cyclohexylamine hydrochloride (Intermediate A) (20 mg, 0.0543 mmol) and 2-hydroxyacetic acid.

Example 11 Trans-N-{4-[2-(4-Benzo[1,3]dioxol-4-yl-piperazin-1-yl)-ethyl]-cyclohexyl}-benzamide

The title compound, white solid (17 mg, 72%), MS (ISP) m/z=436.3 [(M+H)⁺], was prepared in accordance with the general method of example 1 from Trans-4-[2-(4-Benzo[1,3]dioxol-4-yl-piperazin-1-yl)-ethyl]-cyclohexylamine hydrochloride (Intermediate A) (20 mg, 0.0543 mmol) and benzoic acid.

Example 12 Trans-{4-[2-(4-Benzo[1,3]dioxol-4-yl-piperazin-1-yl)-ethyl]-cyclohexyl}-carbamic acid methyl ester

The title compound was prepared from Trans-4-[2-(4-Benzo[1,3]dioxol-4-yl-piperazin-1-yl)-ethyl]-cyclohexylamine hydrochloride (Intermediate A) (25 mg, 0.068 mmol) and triethylamine (20.6 mg, 28.4 μl, 204 μmol) in dichloromethane (1 mL). Methyl carbonochloridate (7.06 mg, 5.78 μl, 0.075 μmol) was added to the mixture stirring at 0° C. The ice bath was removed and the reaction mixture was stirred for 1 hour at room temp. The reaction was diluted with dichloromethane and quenched with sat NaHCO₃ (4 mL). The aqueous layer was extracted with DCM (1×5 mL). The organic layers were dried over MgSO₄ and concentrated in vacuo. The crude material was purified by flash chromatography (silica gel, 10 g, 0% to 15% MeOH in dichloromethane) to yield the title compound as a white solid (9 mg, 34%), MS (ISP) m/z=390.3 [(M+H)⁺].

Example 13 Trans-N-{4-[2-(4-Benzo[1,3]dioxol-4-yl-piperazin-1-yl)-ethyl]-cyclohexyl}-2-(3-methyl-isoxazol-5-yl)-acetamide

The title compound, white solid (17 mg, 54%), MS (ISP) m/z=455.5 [(M+H)⁺], was prepared in accordance with the general method of example 1 from Trans-4-[2-(4-Benzo[1,3]dioxol-4-yl-piperazin-1-yl)-ethyl]-cyclohexylamine hydrochloride (Intermediate A) (25.8 mg, 0.070 mmol) and 2-(3-methyl-isoxazol-5-yl)acetic acid.

Example 14 Trans-N-{4-[2-(4-Benzo[1,3]dioxol-4-yl-piperazin-1-yl)-ethyl]-cyclohexyl}-2-cyano-acetamide

The title compound, white solid (9 mg, 32%), MS (ISP) m/z=399.5 [(M+H)⁺], was prepared in accordance with the general method of example 1 from Trans-4-[2-(4-Benzo[1,3]dioxol-4-yl-piperazin-1-yl)-ethyl]-cyclohexylamine hydrochloride (Intermediate A) (25.8 mg, 0.070 mmol) and 2-(3-methylisoxazol-5-yl)acetic acid

Example 15 Trans-N-{4-[2-(4-Benzo[1,3]dioxol-4-yl-piperazin-1-yl)-ethyl]-cyclohexyl}-2-(1-hydroxy-cyclohexyl)-acetamide

The title compound, off-white solid (13.4 mg, 40%), MS (ISP) m/z=472.5 [(M+H)⁺], was prepared in accordance with the general method of example 1 from Trans-4-[2-(4-Benzo[1,3]dioxol-4-yl-piperazin-1-yl)-ethyl]-cyclohexylamine hydrochloride (Intermediate A) (25.8 mg, 0.070 mmol) and 2-(1-hydroxycyclohexyl)acetic acid.

Example 16 Trans-N-{4-[2-(4-Benzo[1,3]dioxol-4-yl-piperazin-1-yl)-ethyl]-cyclohexyl}-3,3,3-trifluoro-propionamide

The title compound, white solid (11 mg, 35%), MS (ISP) m/z=442.3 [(M+H)⁺], was prepared in accordance with the general method of example 1 from Trans-4-[2-(4-Benzo[1,3]dioxol-4-yl-piperazin-1-yl)-ethyl]-cyclohexylamine hydrochloride (Intermediate A) (25.8 mg, 0.070 mmol) and 3,3,3-trifluoropropanoic acid.

Example 17 Trans-N-{4-[2-(4-Benzo[1,3]dioxol-4-yl-piperazin-1-yl)-ethyl]-cyclohexyl}-isobutyramide

The title compound, white solid (10 mg, 35%), MS (ISP) m/z=402.4 [(M+H)⁺], was prepared in accordance with the general method of example 1 from Trans-4-[2-(4-Benzo[1,3]dioxol-4-yl-piperazin-1-yl)-ethyl]-cyclohexylamine hydrochloride (Intermediate A) (25.8 mg, 0.070 mmol) and isobutyric acid.

Example 18 Trans-N-{4-[2-(4-Benzo[1,3]dioxol-4-yl-piperazin-1-yl)-ethyl]-cyclohexyl}-3-methyl-butyramide

The title compound, white solid (8.2 mg, 28%), MS (ISP) m/z=416.5 [(M+H)⁺], was prepared in accordance with the general method of example 1 from Trans-4-[2-(4-Benzo[1,3]dioxol-4-yl-piperazin-1-yl)-ethyl]-cyclohexylamine hydrochloride (Intermediate A) (25.8 mg, 0.070 mmol) and 3-methylbutanoic acid.

Example 19 Trans-N-{4-[2-(4-Benzo[1,3]dioxol-4-yl-piperazin-1-yl)-ethyl]-cyclohexyl}-butyramide

The title compound, white solid (9 mg, 31%), MS (ISP) m/z=402.3 [(M+H)⁺], was prepared in accordance with the general method of example 1 from Trans-4-[2-(4-Benzo[1,3]dioxol-4-yl-piperazin-1-yl)-ethyl]-cyclohexylamine hydrochloride (Intermediate A) (25.8 mg, 0.070 mmol) and butyric acid.

Example 20 Trans-2,2-Difluoro-cyclopropanecarboxylic acid {4-[2-(4-benzo[1,3]dioxol-4-yl-piperazin-1-yl)-ethyl]-cyclohexyl}-amide

The title compound, white solid (5 mg, 15%), MS (ISP) m/z=436.3 [(M+H)⁺], was prepared in accordance with the general method of example 1 from Trans-4-[2-(4-Benzo[1,3]dioxol-4-yl-piperazin-1-yl)-ethyl]-cyclohexylamine hydrochloride (Intermediate A) (25.8 mg, 0.070 mmol) and 2,2-difluorocyclopropanecarboxylic acid

Example 21 Trans-N-{4-[2-(4-Benzo[1,3]dioxol-4-yl-piperazin-1-yl)-ethyl]-cyclohexyl}-3-methoxy-butyramide

The title compound, white solid (8 mg, 26%), MS (ISP) m/z=432.4 [(M+H)⁺], was prepared in accordance with the general method of example 1 from Trans-4-[2-(4-Benzo[1,3]dioxol-4-yl-piperazin-1-yl)-ethyl]-cyclohexylamine hydrochloride (Intermediate A) (25.8 mg, 0.070 mmol) and 3-methoxybutanoic acid

Example 22 Trans-N-{4-[2-(4-Benzo[1,3]dioxol-4-yl-piperazin-1-yl)-ethyl]-cyclohexyl}-2-oxetan-3-yl-acetamide

The title compound, white solid (15.4 mg, 51.2%), MS (ISP) m/z=430.5 [(M+H)⁺], mp 190° C., was prepared in accordance with the general method of example 1 from Trans-4-[2-(4-Benzo[1,3]dioxol-4-yl-piperazin-1-yl)-ethyl]-cyclohexylamine hydrochloride (Intermediate A) (25.8 mg, 0.070 mmol) and methyl 2-(oxetan-3-yl)acetate prepared from Oxetan-3-ylidene-acetic acid methyl ester as reported on WO2010031735. (example 47)

Example 23 Trans-N-{4-[2-(4-Benzo[1,3]dioxol-4-yl-piperazin-1-yl)-ethyl]-cyclohexyl}-2-((1R,3R)-3-methoxy-cyclopentyl)-acetamide

The title compound, white solid (14 mg, 42%), MS (ISP) m/z=472.6 [(M+H)⁺], was prepared in accordance with the general method of example 1 from Trans-4-[2-(4-Benzo[1,3]dioxol-4-yl-piperazin-1-yl)-ethyl]-cyclohexylamine hydrochloride (Intermediate A) (25.8 mg, 0.070 mmol) and methyl 2-((1R,3R)-3-methoxycyclopentyl)acetate

Example 24 Trans-N-{4-[2-(4-Benzo[1,3]dioxol-4-yl-piperazin-1-yl)-ethyl]-cyclohexyl}-2-hydroxy-2-methyl-propionamide

The title compound, white solid (11.2 mg, 38.3%), MS (ISP) m/z=418.5 [(M+H)⁺], was prepared in accordance with the general method of example 1 from Trans-4-[2-(4-Benzo[1,3]dioxol-4-yl-piperazin-1-yl)-ethyl]-cyclohexylamine hydrochloride (Intermediate A) (25.8 mg, 0.070 mmol) and 2-hydroxy-2-methylpropanoic acid.

Example 25 Trans(S)—N-{4-[2-(4-Benzo[1,3]dioxol-4-yl-piperazin-1-yl)-ethyl]-cyclohexyl}-2-methoxy-propionamide

The title compound, white solid (10.2 mg, 35%), MS (ISP) m/z=418.5 [(M+H)⁺], was prepared in accordance with the general method of example 1 from Trans-4-[2-(4-Benzo[1,3]dioxol-4-yl-piperazin-1-yl)-ethyl]-cyclohexylamine hydrochloride (Intermediate A) (25.8 mg, 0.070 mmol) and (S)-2-methoxypropanoic acid

Example 26 Trans(R)—N-{4-[2-(4-Benzo[1,3]dioxol-4-yl-piperazin-1-yl)-ethyl]-cyclohexyl}-2-methoxy-propionamide

The title compound, white solid (21 mg, 72%), MS (ISP) m/z=418.3 [(M+H)⁺], was prepared in accordance with the general method of example 1 from Trans-4-[2-(4-Benzo[1,3]dioxol-4-yl-piperazin-1-yl)-ethyl]-cyclohexylamine hydrochloride (Intermediate A) (25.8 mg, 0.070 mmol?) and (R)-2-methoxypropanoic acid

Example 27 Trans-N-{4-[2-(4-Benzo[1,3]dioxol-4-yl-piperazin-1-yl)-ethyl]-cyclohexyl}-3-hydroxy-3-methyl-butyramide

The title compound, white solid (15 mg, 49.7%), MS (ISP) m/z=432.4 [(M+H)⁺], was prepared in accordance with the general method of example 1 from Trans-4-[2-(4-Benzo[1,3]dioxol-4-yl-piperazin-1-yl)-ethyl]-cyclohexylamine hydrochloride (Intermediate A) (25.8 mg, 0.070 mmol) and 3-hydroxy-3-methylbutanoic acid.

Example 28 Trans-N-{4-[2-(4-Benzo[1,3]dioxol-4-yl-piperazin-1-yl)-ethyl]-cyclohexyl}-2-(1-hydroxy-cyclobutyl)-acetamide

The title compound, white solid (21 mg, 69.7%), MS (ISP) m/z=444.3 [(M+H)⁺], was prepared in accordance with the general method of example 1 from Trans-4-[2-(4-Benzo[1,3]dioxol-4-yl-piperazin-1-yl)-ethyl]-cyclohexylamine hydrochloride (Intermediate A) (25 mg, 0.068 mmol) and 1-hydroxy-cyclopropane-carboxylic acid. The 1-hydroxy-cyclopropane-carboxylic acid was prepared from ethyl 2-(1-hydroxycyclobutyl)acetate (16.1 mg, 0.102 mmol) by saponification using LiOH (3.66 mg, 0.153 mmol) stirring 4 hours in a solvent mixture of THF (200 μl), methanol (200 μl) and water (200 μl). The crude 1-hydroxy-cyclopropane-carboxylic acid used on the coupling was obtained after acidifying the reaction to pH 4 with HCl 2N. and concentrating the reaction mixture in vacuo.

Example 29 Trans-1-Hydroxy-cyclopropanecarboxylic acid {4-[2-(4-benzo[1,3]dioxol-4-yl-piperazin-1-yl)-ethyl]-cyclohexyl}-amide

The title compound, white solid (78 mg, 69.1%), MS (ISP) m/z=416.3 [(M+H)⁺], was prepared in accordance with the general method of example 1 from Trans-4-[2-(4-Benzo[1,3]dioxol-4-yl-piperazin-1-yl)-ethyl]-cyclohexylamine hydrochloride (Intermediate A) (100 mg, 0.272 mmol) and 1-hydroxycyclopropanecarboxylic acid.

Example 30 Trans-N-{4-[2-(4-Benzo[1,3]dioxol-4-yl-piperazin-1-yl)-ethyl]-cyclohexyl}-2-(S) or (R)-tetrahydro-pyran-2-yl-acetamide

The title compound, white solid (22.4 mg, 78%), MS (ISP) m/z=458.5 [(M+H)⁺], was prepared in accordance with the general method of example 1 from Trans-4-[2-(4-Benzo[1,3]dioxol-4-yl-piperazin-1-yl)-ethyl]-cyclohexylamine hydrochloride (Intermediate A) (25 mg, 0.068 mmol) and chiral (S) (or R)-2-(tetrahydro-2H-pyran-2-yl)acetic acid, obtained from chiral separation of rac-2-(tetrahydro-2H-pyran-2-yl)benzyl ester (using a Chiralpak AD column with 25% of EtOH in heptane) and hydrogenation to remove the benzyl ester.

Example 31 Trans-N-{4-[2-(4-Benzo[1,3]dioxol-4-yl-piperazin-1-yl)-ethyl]-cyclohexyl}-2-(R) or (S)-tetrahydro-pyran-2-yl-acetamide

The title compound, white solid (22.5 mg, 72.3%), MS (ISP) m/z=458.4 [(M+H)⁺], was prepared in accordance with the general method of example 1 from Trans-4-[2-(4-Benzo[1,3]dioxol-4-yl-piperazin-1-yl)-ethyl]-cyclohexylamine hydrochloride (Intermediate A) (25 mg, 0.068 mmol) and chiral (R) (or S)-2-(tetrahydro-2H-pyran-2-yl)acetic acid obtained from chiral separation of the racemic acid mixture.

Example 32 Trans-N-{4-[2-(4-Benzo[1,3]dioxol-4-yl-piperazin-1-yl)-ethyl]-cyclohexyl}-2-(S) or (R)-tetrahydro-pyran-3-yl-acetamide

The title compound, white solid (22.6 mg, 72.6%), MS (ISP) m/z=458.5 [(M+H)⁺], was prepared in accordance with the general method of example 1 from Trans-4-[2-(4-Benzo[1,3]dioxol-4-yl-piperazin-1-yl)-ethyl]-cyclohexylamine hydrochloride (Intermediate A) (25 mg, 0.068 mmol) and chiral (S) or (R)-2-(tetrahydro-2H-pyran-3-yl)acetic acid obtained from chiral separation of rac-2-(tetrahydro-2H-pyran-3-yl)benzyl ester (using a Chiralpak AD column with 25% of EtOH in heptane) and hydrogenation to remove the benzyl ester.

Example 33 Trans-N-{4-[2-(4-Benzo[1,3]dioxol-4-yl-piperazin-1-yl)-ethyl]-cyclohexyl}-2-(R) or (S)-tetrahydro-pyran-3-yl-acetamide

The title compound, white solid (21.6 mg, 69.4%), MS (ISP) m/z=458.4 [(M+H)⁺], was prepared in accordance with the general method of example 1 from Trans-4-[2-(4-Benzo[1,3]dioxol-4-yl-piperazin-1-yl)-ethyl]-cyclohexylamine hydrochloride (Intermediate A) (25 mg, 0.068 mmol) and chiral (R) or (S)-2-(tetrahydro-2H-pyran-3-yl)acetic acid obtained from the chiral separation.

Example 34 Trans-N-{4-[2-(4-Benzo[1,3]dioxol-4-yl-piperazin-1-yl)-ethyl]-cyclohexyl}-methanesulfonamide

In a 5 mL round-bottomed flask, Trans-4-[2-(4-Benzo[1,3]dioxol-4-yl-piperazin-1-yl)-ethyl]-cyclohexylamine hydrochloride (Intermediate A) (25 mg, 0.068 mmol) was solved in dichloromethane (500 μl) to give a white suspension. N,N-diisopropylamine (26.3 mg, 35.6 μl, 0.204 mmol) was added. and after 10 min stirring, methanesulfonyl chloride (11.7 mg, 7.89 μl, 0.102 mmol) was added and the reaction mixture was stirred over night at room temp. The reaction was quenched with 15 mL of saturated NaHCO₃ and extracted with dichloromethane (3×20 mL). The organic layers were dried over MgSO₄ and concentrated in vacuo. The crude material was purified by flash chromatography (silica gel, 10 g, 0% to 15% MeOH in dichloromethane) to yield the title compound as white solid (18 mg, 64.3%), MS (ISP) m/z=410.3 [(M+H)⁺].

Example 35 1-Hydroxy-cyclobutanecarboxylic acid-trans-N-{4-[2-(4-benzo[1,3]dioxol-4-yl-piperazin-1-yl)-ethyl]-cyclohexyl}-amide

The title compound, white solid (15 mg, 48.7%), MS (ISP) m/z=430.2 [(M+H)⁺], was prepared in accordance with the general method of example 1 from Trans-4-[2-(4-Benzo[1,3]dioxol-4-yl-piperazin-1-yl)-ethyl]-cyclohexylamine trihydrochloride (Intermediate A) (30 mg, 68.1 mmol) and 1-hydroxycyclobutancarboxylic acid.

Example 36 1-Hydroxy-cyclopentanecarboxylic acid-trans-N-{4-[2-(4-benzo[1,3]dioxol-4-yl-piperazin-1-yl)-ethyl]-cyclohexyl}-amide

The title compound, white solid (17 mg, 53.5%), MS (ISP) m/z=444.3 [(M+H)⁺], was prepared in accordance with the general method of example 1 from Trans-4-[2-(4-Benzo[1,3]dioxol-4-yl-piperazin-1-yl)-ethyl]-cyclohexylamine trihydrochloride (Intermediate A) (30 mg, 68.1 mmol) and 1-hydroxycyclopentanecarboxylic acid.

Example 37 1-Hydroxy-cyclohexanecarboxylic acid-trans-N-{4-[2-(4-benzo[1,3]dioxol-4-yl-piperazin-1-yl)-ethyl]-cyclohexyl}-amide

The title compound, white solid (20 mg, 61%), MS (ISP) m/z=458.3 [(M+H)⁺], was prepared in accordance with the general method of example 1 from Trans-4-[2-(4-Benzo[1,3]dioxol-4-yl-piperazin-1-yl)-ethyl]-cyclohexylamine trihydrochloride (Intermediate A) (30 mg, 68.1 mmol) and 1-hydroxycyclohexanecarboxylic acid.

Example 38 Trans-N-{4-[2-(4-Benzo[1,3]dioxol-4-yl-piperazin-1-yl)-ethyl]-cyclohexyl}-2-hydroxy-butyramide

The title compound, white solid (15 mg, 50.1%), MS (ISP) m/z=418.3 [(M+H)⁺], was prepared in accordance with the general method of example 1 from Trans-4-[2-(4-Benzo[1,3]dioxol-4-yl-piperazin-1-yl)-ethyl]-cyclohexylamine trihydrochloride (Intermediate A) (30 mg, 68.1 mmol) and 2-hydroxybutanoic acid.

Example 39 (R)-Trans-N-{4-[2-(4-Benzo[1,3]dioxol-4-yl-piperazin-1-yl)-ethyl]-cyclohexyl}-2-hydroxy-3-methyl-butyramide

The title compound, white solid (12.1 mg, 34.4%), MS (ISP) m/z=432.4 [(M+H)⁺], was prepared in accordance with the general method of example 1 from Trans-4-[2-(4-Benzo[1,3]dioxol-4-yl-piperazin-1-yl)-ethyl]-cyclohexylamine hydrochloride (Intermediate A) (30 mg, 81.5 mmol) and (R)-2-hydroxy-3-methylbutanoic acid.

Example 40 (S)-Trans-N-{4-[2-(4-Benzo[1,3]dioxol-4-yl-piperazin-1-yl)-ethyl]-cyclohexyl}-2-hydroxy-3-methyl-butyramide

The title compound, white solid (9 mg, 25.6%), MS (ISP) m/z=432.4 [(M+H)⁺], was prepared in accordance with the general method of example 1 from Trans-4-[2-(4-Benzo[1,3]dioxol-4-yl-piperazin-1-yl)-ethyl]-cyclohexylamine hydrochloride (Intermediate A) (30 mg, 81.5 mmol) and (S)-2-hydroxy-3-methylbutanoic acid.

Example 41 1-Methoxy-cyclohexanecarboxylic acid-Trans-N-{4-[2-(4-benzo[1,3]dioxol-4-yl-piperazin-1-yl)-ethyl]-cyclohexyl}-amide

The title compound, white solid (17.4 mg, 40.8%), MS (ISP) m/z=472.1 [(M+H)⁺], was prepared in accordance with the general method of example 1 from Trans-4-[2-(4-Benzo[1,3]dioxol-4-yl-piperazin-1-yl)-ethyl]-cyclohexylamine hydrochloride (Intermediate A) (30 mg, 81.5 mmol) and 1-Methoxycyclohexane-1-carboxylic acid.

Example 42 (R)-Trans-N-{4-[2-(4-Benzo[1,3]dioxol-4-yl-piperazin-1-yl)-ethyl]-cyclohexyl}-2-hydroxy-propionamide

The title compound, white solid (88.4 mg, 40.3%), MS (ISP) m/z=404.4 [(M+H)⁺], was prepared in accordance with the general method of example 1 from Trans-4-[2-(4-Benzo[1,3]dioxol-4-yl-piperazin-1-yl)-ethyl]-cyclohexylamine hydrochloride (Intermediate A) (200 mg, 544 mmol) and (R)-2-hydroxypropanoic acid.

Example 43 Tetrahydro-pyran-4-carboxylic acid-trans-N-{4-[2-(4-benzo[1,3]dioxol-4-yl-piperazin-1-yl)-ethyl]-cyclohexyl}-amide

The title compound, white solid (29.5 mg, 81.6%), MS (ISP) m/z=444.3 [(M+H)⁺], was prepared in accordance with the general method of example 1 from Trans-4-[2-(4-Benzo[1,3]dioxol-4-yl-piperazin-1-yl)-ethyl]-cyclohexylamine hydrochloride (Intermediate A) (30 mg, 81.5 mmol) and tetrahydro-2H-pyran-4-carboxylic acid.

Example 44 Tetrahydro-furan-2-carboxylic acid-trans-N-{4-[2-(4-benzo[1,3]dioxol-4-yl-piperazin-1-yl)-ethyl]-cyclohexyl}-amide

The title compound, white solid (24.3 mg, 69.4%), MS (ISP) m/z=430 [(M+H)⁺], was prepared in accordance with the general method of example 1 from Trans-4-[2-(4-Benzo[1,3]dioxol-4-yl-piperazin-1-yl)-ethyl]-cyclohexylamine hydrochloride (Intermediate A) (30 mg, 81.5 mmol) and tetrahydrofuran-2-carboxylic acid.

Example 45 Trans-N-{4-[2-(4-Benzo[1,3]dioxol-4-yl-piperazin-1-yl)-ethyl]-cyclohexyl}-4-morpholin-4-yl-benzamide

The title compound, white solid (16.3 mg, 38.4%), MS (ISP) m/z=421.4 [(M+H)⁺], was prepared in accordance with the general method of example 1 from Trans-4-[2-(4-Benzo[1,3]dioxol-4-yl-piperazin-1-yl)-ethyl]-cyclohexylamine hydrochloride (Intermediate A) (30 mg, 81.5 mmol) and 4-morpholinobenzoic acid.

Example 46 Trans-N-{4-[2-(4-Benzo[1,3]dioxol-4-yl-piperazin-1-yl)-ethyl]-cyclohexyl}-4-fluoro-benzamide

The title compound, white solid (23.8 mg, 64.4%), MS (ISP) m/z=454.3 [(M+H)⁺], was prepared in accordance with the general method of example 1 from Trans-4-[2-(4-Benzo[1,3]dioxol-4-yl-piperazin-1-yl)-ethyl]-cyclohexylamine hydrochloride (Intermediate A) (30 mg, 81.5 mmol) and 4-fluorobenzoic acid.

Example 47

Quinoline-4-carboxylic acid-trans-N-{4-[2-(4-benzo[1,3]dioxol-4-yl-piperazin-1-yl)-ethyl]-cyclohexyl}-amide

The title compound, white solid (14.2 mg, 35.8%), MS (ISP) m/z=487.4 [(M+H)⁺], was prepared in accordance with the general method of example 1 from Trans-4-[2-(4-Benzo[1,3]dioxol-4-yl-piperazin-1-yl)-ethyl]-cyclohexylamine hydrochloride (Intermediate A) (x mg, x mmol) and quinoline-4-carboxylic acid.

Example 48 Trans-N-{4-[2-(4-Benzo[1,3]dioxol-4-yl-piperazin-1-yl)-ethyl]-cyclohexyl}-nicotinamide

The title compound, white solid (18.3 mg, 51.4%), MS (ISP) m/z=437.3 [(M+H)⁺], was prepared in accordance with the general method of example 1 from Trans-4-[2-(4-Benzo[1,3]dioxol-4-yl-piperazin-1-yl)-ethyl]-cyclohexylamine hydrochloride (Intermediate A) (30 mg, 81.5 mmol) and nicotinic acid.

Example 49 2,3-Dihydro-benzo[1,4]dioxine-6-carboxylic acid-trans-N-{4-[2-(4-benzo[1,3]dioxol-4-yl-piperazin-1-yl)-ethyl]-cyclohexyl}-amide

The title compound, white solid (19 mg, 47.2%), MS (ISP) m/z=494.3 [(M+H)⁺], was prepared in accordance with the general method of example 1 from Trans-4-[2-(4-Benzo[1,3]dioxol-4-yl-piperazin-1-yl)-ethyl]-cyclohexylamine hydrochloride (Intermediate A) (30 mg, 81.5 mmol) and 2,3-dihydrobenzo[b][1,4]dioxine-6-carboxylic acid.

Example 50

Chroman-3-carboxylic acid-trans-N-{4-[2-(4-benzo[1,3]dioxol-4-yl-piperazin-1-yl)-ethyl]-cyclohexyl}-amide

The title compound, white solid (26 mg, 64.9%), MS (ISP) m/z=492.3 [(M+H)⁺], was prepared in accordance with the general method of example 1 from Trans-4-[2-(4-Benzo[1,3]dioxol-4-yl-piperazin-1-yl)-ethyl]-cyclohexylamine hydrochloride (Intermediate A) (30 mg, 81.5 mmol) and chroman-3-carboxylic acid.

Example 51 2-Benzo[1,3]dioxol-5-yl-trans-N-{4-[2-(4-benzo[1,3]dioxol-4-yl-piperazin-1-yl)-ethyl]-cyclohexyl}-acetamide

The title compound, white solid (26 mg, 64.6%), MS (ISP) m/z=494.3 [(M+H)⁺], was prepared in accordance with the general method of example 1 from Trans-4-[2-(4-Benzo[1,3]dioxol-4-yl-piperazin-1-yl)-ethyl]-cyclohexylamine hydrochloride (Intermediate A) (30 mg, 81.5 mmol) and 2-(benzo[d][1,3]dioxol-5-yl)acetic acid.

Example 52 1,1-Dioxo-tetrahydro-1,6-thiophene-3-carboxylic acid-trans-N-{4-[2-(4-benzo[1,3]dioxol-4-yl-piperazin-1-yl)-ethyl]-cyclohexyl}-amide

The title compound, white solid (22.4 mg, 57.5%), MS (ISP) m/z=478.1 [(M+H)⁺], was prepared in accordance with the general method of example 1 from Trans-4-[2-(4-Benzo[1,3]dioxol-4-yl-piperazin-1-yl)-ethyl]-cyclohexylamine hydrochloride (Intermediate A) (30 mg, 81.5 mmol) and 1,1-Dioxo-tetrahydro-1lambda6-thiophene-3-carboxylic acid.

Example 53 N-trans-{4-[2-(4-Benzo[1,3]dioxol-4-yl-piperazin-1-yl)-ethyl]-cyclohexyl}-2-(tetrahydro-pyran-4-yl)-acetamide

The title compound, white solid (21 mg, 56.3%), MS (ISP) m/z=458.3 [(M+H)⁺], was prepared in accordance with the general method of example 1 from Trans-4-[2-(4-Benzo[1,3]dioxol-4-yl-piperazin-1-yl)-ethyl]-cyclohexylamine hydrochloride (Intermediate A) (30 mg, 81.5 mmol) and 2-(tetrahydro-2H-pyran-4-yl)acetic acid.

Example 54 Cyclobutanecarboxylic acid-trans-N-{4-[2-(4-benzo[1,3]dioxol-4-yl-piperazin-1-yl)-ethyl]-cyclohexyl}-amide

The title compound, white solid (22.1 mg, 65.5%), MS (ISP) m/z=414.2 [(M+H)⁺], was prepared in accordance with the general method of example 1 from Trans-4-[2-(4-Benzo[1,3]dioxol-4-yl-piperazin-1-yl)-ethyl]-cyclohexylamine hydrochloride (Intermediate A) (30 mg, 81.5 mmol) and cyclobutanecarboxylic acid.

Example 55 Trans-N-{4-[2-(4-Benzo[1,3]dioxol-4-yl-piperazin-1-yl)-ethyl]-cyclohexyl}-2-methanesulfonyl-acetamide

The title compound, white solid (22.6 mg, 61.4%), MS (ISP) m/z=452.1 [(M+H)⁺], was prepared in accordance with the general method of example 1 from Trans-4-[2-(4-Benzo[1,3]dioxol-4-yl-piperazin-1-yl)-ethyl]-cyclohexylamine hydrochloride (Intermediate A) (30 mg, 81.5 mmol) and 2-(methylsulfonyl)acetic acid.

Example 56 Trans-N-{4-[2-(4-Benzo[1,3]dioxol-4-yl-piperazin-1-yl)-ethyl]-cyclohexyl}-2-(4-methoxy-cyclohexyl)-acetamide

The title compound, white solid (27.1 mg, 68.4%), MS (ISP) m/z=486.4 [(M+H)⁺], was prepared in accordance with the general method of example 1 from Trans-4-[2-(4-Benzo[1,3]dioxol-4-yl-piperazin-1-yl)-ethyl]-cyclohexylamine hydrochloride (Intermediate A) (30 mg, 81.5 mmol) and (trans-4-Methoxycyclohexyl)acetic acid (synthesized as described in W2009/013212 p. 73).

Example 57 1-Methyl-piperidine-4-carboxylic acid-trans-N-{4-[2-(4-benzo[1,3]dioxol-4-yl-piperazin-1-yl)-ethyl]-cyclohexyl}-amide

The title compound, white solid (26.2 mg, 67.5%), MS (ISP) m/z=457.3 [(M+H)⁺], was prepared in accordance with the general method of example 1 from Trans-4-[2-(4-Benzo[1,3]dioxol-4-yl-piperazin-1-yl)-ethyl]-cyclohexylamine hydrochloride (Intermediate A) (30 mg, 92.5 mmol) and 1-methylpiperidine-4-carboxylic acid.

Example 58 3-Methyl-oxetane-3-carboxylic acid-trans-N-{4-[2-(4-benzo[1,3]dioxol-4-yl-piperazin-1-yl)-ethyl]-cyclohexyl}-amide

The title compound, white solid (19 mg, 52%), MS (ISP) m/z=430.2 [(M+H)⁺], was prepared in accordance with the general method of example 1 from Trans-4-[2-(4-Benzo[1,3]dioxol-4-yl-piperazin-1-yl)-ethyl]-cyclohexylamine hydrochloride (Intermediate A) (30 mg, 81.5 mmol) and 3-methyloxetane-3-carboxylic acid.

Example 59 Trans-N-{4-[2-(4-Benzo[1,3]dioxol-4-yl-piperazin-1-yl)-ethyl]-cyclohexyl}-4-cyano-benzamide

The title compound, white solid (22.6 mg, 60.2%), MS (ISP) m/z=461.3 [(M+H)⁺], was prepared in accordance with the general method of example 1 from Trans-4-[2-(4-Benzo[1,3]dioxol-4-yl-piperazin-1-yl)-ethyl]-cyclohexylamine hydrochloride (Intermediate A) (30 mg, 81.5 mmol) and 4-cyanobenzoic acid.

Example 60 3-Chloro-cyclobutanecarboxylic acid-trans-N-{4-[2-(4-benzo[1,3]dioxol-4-yl-piperazin-1-yl)-ethyl]-cyclohexyl}-amide

The title compound, white solid (13 mg, 35.6%), MS (ISP) m/z=448.2 [(M+H)⁺], was prepared in accordance with the general method of example 1 from Trans-4-[2-(4-Benzo[1,3]dioxol-4-yl-piperazin-1-yl)-ethyl]-cyclohexylamine hydrochloride (Intermediate A) (30 mg, 81.5 mmol) and 3-chlorocyclobutanecarboxylic acid.

Example 61 Trans-N-{4-[2-(4-Benzo[1,3]dioxol-4-yl-piperazin-1-yl)-ethyl]-cyclohexyl}-2-(4-methyl-piperazin-1-yl)-acetamide

The title compound, white solid (22.5 mg, 58.5%), MS (ISP) m/z=472.3 [(M+H)⁺], was prepared in accordance with the general method of example 1 from Trans-4-[2-(4-Benzo[1,3]dioxol-4-yl-piperazin-1-yl)-ethyl]-cyclohexylamine hydrochloride (Intermediate A) (30 mg, 81.5 mmol) and 2-(4-methylpiperazin-1-yl)acetic acid.

Example 62 1-Methoxy-cyclopropanecarboxylic acid-trans-N-{4-[2-(4-benzo[1,3]dioxol-4-yl-piperazin-1-yl)-ethyl]-cyclohexyl}-amide

To trans-1-Hydroxy-cyclopropanecarboxylic acid {4-[2-(4-benzo[1,3]dioxol-4-yl-piperazin-1-yl)-ethyl]-cyclohexyl}-amide (20 mg, 48.1 μmol, Eq: 1.00) in THF (500 μl) was added NaH (3.37 mg, 84.2 μmol, Eq: 1.75) and methyl iodide (17.1 mg, 7.52 μl, 120 μmol, Eq: 2.5). After 2 hours the reaction mixture was diluted with water (300 ul). The crude reaction mixture was concentrated in vacuo. The residue was suspended with 5 mL sat NaHCO₃ and extracted with dichloromethane (2×10 mL). The organic layers were dried over MgSO₄ and concentrated in vacuo. The crude material was purified by flash chromatography (silica gel, 10 g, 0% to 15% MeOH in dichloromethane) to yield the title compound as an off-white solid (12.1 mg, 58.5%), MS (ISP) m/z=430.2 [(M+H)⁺].

Example 63 Trans-N-{4-[2-(4-Benzo[1,3]dioxol-4-yl-piperazin-1-yl)-ethyl]-cyclohexyl}-2-methoxy-2-methyl-propionamide

The title compound, white solid (3 mg, 13.1%), MS (ISP) m/z=432.4 [(M+H)⁺], was prepared in accordance with the general method of example 62 from N-{4-[2-(4-Benzo[1,3]dioxol-4-yl-piperazin-1-yl)-ethyl]-cyclohexyl}-2-hydroxy-2-methyl-propionamide (20 mg, 47.9 mmol) and methyl iodide.

Example 64 (R)-trans-N-{4-[2-(4-Benzo[1,3]dioxol-4-yl-piperazin-1-yl)-ethyl]-cyclohexyl}-2-methoxy-3-methyl-butyramide

The title compound, white solid (6 mg, 50.5%), MS (ISP) m/z=446.3 [(M+H)⁺], was prepared in accordance with the general method of example 62 from (R)-trans-N-{4-[2-(4-Benzo[1,3]dioxol-4-yl-piperazin-1-yl)-ethyl]-cyclohexyl}-2-hydroxy-3-methyl-butyramide (11.5 mg, 26.6 mmol) and methyl iodide.

Example 65 (S)-trans-N-{4-[2-(4-Benzo[1,3]dioxol-4-yl-piperazin-1-yl)-ethyl]-cyclohexyl}-2-methoxy-3-methyl-butyramide

The title compound, white solid (5.7 mg, 69%), MS (ISP) m/z=446.4 [(M+H)⁺], was prepared in accordance with the general method of example 62 from (S)-trans-N-{4-[2-(4-Benzo[1,3]dioxol-4-yl-piperazin-1-yl)-ethyl]-cyclohexyl}-2-hydroxy-3-methyl-butyramide (8 mg, 18.5 mmol) and methyl iodide.

Example 66 2,2,2-Trifluoro-ethanesulfonic acid-trans-N-{4-[2-(4-benzo[1,3]dioxol-4-yl-piperazin-1-yl)-ethyl]-cyclohexyl}-amide

To a stirred mixture of N-trans-4-[2-(4-Benzo[1,3]dioxol-4-yl-piperazin-1-yl)-ethyl]-cyclohexylamine hydrochloride (Intermediate A) (30 mg, 81.5 μmol, Eq: 1.00) in dichloromethane (500 μl) was added at room temperature N,N-diisopropylethylamine (31.6 mg, 42.7 μl, 245 μmol, Eq: 3) and 2,2,2-trifluoroethanesulfonyl chloride (22.3 mg mg, 122 μmol). The mixture was allowed to stir at room temperature over night. The crude reaction diluted with 5 mL sat NaHCO₃ and extracted with DCM (2×10 mL). The organic layers were dried over MgSO₄ and concentrated in vacuo. The crude material was purified by flash chromatography (silica gel, 10 g, 0% to 10% MeOH in DCM) to yield the title compound as an white solid (16 mg, 41.1%), MS (ISP) m/z=478.1 [(M+H)⁺].

Example 67 N-trans-{4-[2-(4-Benzo[1,3]dioxol-4-yl-piperazin-1-yl)-ethyl]-cyclohexyl}-benzenesulfonamide

The title compound, white solid (24 mg, 62.4%), MS (ISP) m/z=472.3 [(M+H)⁺], was prepared in accordance with the general method of example 66 from N-trans-4-[2-(4-Benzo[1,3]dioxol-4-yl-piperazin-1-yl)-ethyl]-cyclohexylamine hydrochloride (Intermediate A) (30 mg, 81.5 μmol) and benzenesulfonyl chloride

Example 68 N-trans-{4-[2-(4-Benzo[1,3]dioxol-4-yl-piperazin-1-yl)-ethyl]-cyclohexyl}-4-fluoro-benzenesulfonamide

The title compound, white solid (22 mg, 55.1%), MS (ISP) m/z=490.1 [(M+H)⁺], was prepared in accordance with the general method of example 66 from N-trans-4-[2-(4-Benzo[1,3]dioxol-4-yl-piperazin-1-yl)-ethyl]-cyclohexylamine hydrochloride (Intermediate A) (30 mg, 81.5 μmol) and 4-fluorobenzene-1-sulfonyl chloride

Example 69 1-Methyl-1H-imidazole-4-sulfonic acid-trans-N-{4-[2-(4-benzo[1,3]dioxol-4-yl-piperazin-1-yl)-ethyl]-cyclohexyl}-amide

The title compound, white solid (23 mg, 59.3%), MS (ISP) m/z=476.1 [(M+H)⁺], was prepared in accordance with the general method of example 66 from N-trans-4-[2-(4-Benzo[1,3]dioxol-4-yl-piperazin-1-yl)-ethyl]-cyclohexylamine hydrochloride (Intermediate A) (30 mg, 81.5 μmol) and 1-methyl-1H-imidazole-4-sulfonyl chloride.

Example 70 N-trans-{4-[2-(4-Benzo[1,3]dioxol-4-yl-piperazin-1-yl)-ethyl]-cyclohexyl}-2,2,2-trifluoro-acetamide

To a stirred mixture of N-trans-4-[2-(4-Benzo[1,3]dioxol-4-yl-piperazin-1-yl)-ethyl]-cyclohexylamine hydrochloride (Intermediate A) (30 mg, 81.5 μmol, Eq: 1.00) in dichloromethane (500 μl) at 0° C. was added triethylamine (16.5 mg, 22.7 μl, 163 μmol, Eq: 2) and 2,2,2-trifluoroacetic anhydride (85.6 mg, 56.7 μl, 408 μmol, Eq: 5). The mixture was allowed to stir for 1 hour at 0° C. The reaction mixture was quenched with 10 mL sat NaHCO₃ and extracted with DCM (3×15 mL). The organic layers were dried over MgSO₄ and concentrated in vacuo. The crude material was purified by flash chromatography (silica gel, 100 g, 0% to 10% MeOH in DCM) to yield the title compound as an white solid (23 mg, 66%), MS (ISP) m/z=428.1 [(M+H)⁺].

Example 71 2,3-Dihydro-indole-1-carboxylic acid-trans-N-{4-[2-(4-benzo[1,3]dioxol-4-yl-piperazin-1-yl)-ethyl]-cyclohexyl}-amide

To a stirred mixture of N-trans-4-[2-(4-Benzo[1,3]dioxol-4-yl-piperazin-1-yl)-ethyl]-cyclohexylamine hydrochloride (Intermediate A) (31.1 mg, 85 μmol) in DCM (1 ml) at room temperature N,N-diisopropylethylamine (110 mg, 148 μl, 850 μmol, Eq: 10) and triphosgene (27.7 mg, 93.5 μmol, Eq: 1.1) was added carefully and the solution stirred for minutes at room temperature. Indoline (12.2 mg, 102 μmol, Eq: 1.2) was added and stirred for 30 minutes at room temperature. The reaction mixture was quenched with 10 mL sat NaHCO₃ and extracted with DCM (3×15 mL). The organic layers were dried over MgSO₄ and concentrated in vacuo. The crude material was purified by flash chromatography (silica gel, 100 g, 0% to 10% MeOH in DCM) to yield the title compound as an white solid (27.6 mg, 68.1%), MS (ISP) m/z=477.2 [(M+H)⁺].

Example 72 N-trans-3-{4-[2-(4-Benzo[1,3]dioxol-4-yl-piperazin-1-yl)-ethyl]-cyclohexyl}-1,1-dimethyl-urea

The title compound, white solid (14.7 mg, 42.9%), MS (ISP) m/z=403.5 [(M+H)⁺], was prepared in accordance with the general method of example 71 from N-trans-4-[2-(4-Benzo[1,3]dioxol-4-yl-piperazin-1-yl)-ethyl]-cyclohexylamine hydrochloride (Intermediate A) (31.1 mg, 85 μmol) and dimethylamine hydrochloride

Example 73 N-trans-{4-[2-(4-Benzo[1,3]dioxol-4-yl-piperazin-1-yl)-ethyl]-cyclohexyl}-2-fluoro-acetamide

A mixture of methyl 2-fluoroacetate (11.3 mg, 122 μmol, Eq: 1.5) and KOSiMe₃ (20.9 mg, 163 μmol, Eq: 2) in Dioxane (1 ml) was stirred at room temperature over night. N-trans-4-[2-(4-Benzo[1,3]dioxol-4-yl-piperazin-1-yl)-ethyl]-cyclohexylamine hydrochloride (Intermediate A) (30 mg, 81.5 μmol), N,N-diisopropylethylamine (42.2 mg, 57.0 μl, 326 μmol, Eq: 4) and TBTU (39.3 mg, 122 μmol, Eq: 1.5) were added. Reaction mixture was stirred 4 h at room temperature. The reaction mixture was solved with sat NaHCO₃ (1×10 mL). and extracted with dichloromethane (2×20 mL). The organic layers were dried over MgSO₄ and concentrated in vacuo. The crude material was purified by flash chromatography (silica gel, 100 g, 0% to 20% MeOH in dichloromethane) to yield the title compound as an off-white solid (17.2 mg, 53.9%), MS (ISP) m/z=392.3 [(M+H)⁺].

Example 74 N-trans-{4-[2-(4-Benzo[1,3]dioxol-4-yl-piperazin-1-yl)-ethyl]-cyclohexyl}-2-(3-hydroxymethyl-cyclobutyl)-acetamide

The title compound, white solid (8.8 mg, 17.5%), MS (ISP) m/z=458.3 [(M+H)⁺], was prepared in accordance with the general method of example 73 from N-trans-4-[2-(4-Benzo[1,3]dioxol-4-yl-piperazin-1-yl)-ethyl]-cyclohexylamine hydrochloride (Intermediate A) (30 mg, 81.5 μmol) and Trans-(3-Hydroxymethyl-cyclobutyl)-acetic acid methyl ester.

Example 75 N-trans-1-{4-[2-(4-Benzo[1,3]dioxol-4-yl-piperazin-1-yl)-ethyl]-cyclohexyl}-3-(4-chloro-phenyl)-urea

To a stirred mixture of Trans-4-[2-(4-Benzo[1,3]dioxol-4-yl-piperazin-1-yl)-ethyl]-cyclohexylamine hydrochloride (Intermediate A) (25 mg, 75.4 μmol) in acetonitrile (800 μl) was added 1-chloro-4-isocyanatobenzene (12.7 mg, 83.0 μmol, Eq: 1.1. Reaction mixture was stirred at room temperature over night. The reaction mixture was solved with sat NaHCO₃ (1×10 mL). and extracted with dichloromethane (2×20 mL). The organic layers were dried over MgSO₄ and concentrated in vacuo. The crude material was purified by flash chromatography (silica gel, 10 g, 0% to 20% MeOH in dichloromethane) to yield the title compound as an off-white solid (28.3 mg, 77.4%), MS (ISP) m/z=485.2 [(M+H)+].

Example 76 N-trans-{4-[2-(4-benzo[1,3]dioxol-4-yl-piperazin-1-yl)-ethyl]-cyclohexyl}-N,N-dimethyl-sulfamide

To a stirred mixture of N-trans-4-[2-(4-Benzo[1,3]dioxol-4-yl-piperazin-1-yl)-ethyl]-cyclohexylamine hydrochloride (Intermediate A) (31.3 mg, 85 μmol) in acetonitrile (1 ml) was added dimethylsulfamoyl chloride (18.4 mg, 128 μmol, Eq: 1.5) and DABCO (33.4 mg, 298 μmol, Eq: 3.5). Reaction mixture was stirred at room temperature for 24 hours. The reaction mixture was solved with sat NaHCO₃ (1×10 mL). and extracted with dichloromethane (2×20 mL). The organic layers were dried over MgSO₄ and concentrated in vacuo. The crude material was purified by flash chromatography (silica gel, 10 g, 0% to 20% MeOH in dichloromethane) to yield the title compound as an off-white solid (22.8 mg, 61.2%), MS (ISP) m/z=439.3 [(M+H)+].

Example 77 Morpholine-4-sulfonic acid-trans-N-{4-[2-(4-benzo[1,3]dioxol-4-yl-piperazin-1-yl)-ethyl]-cyclohexyl}-amide

The title compound, white solid (24.6 mg, 60.2%), MS (ISP) m/z=481.2 [(M+H)⁺], was prepared in accordance with the general method of example 76 from N-trans-4-[2-(4-Benzo[1,3]dioxol-4-yl-piperazin-1-yl)-ethyl]-cyclohexylamine hydrochloride (Intermediate A) (30 mg, 81.5 μmol) and morpholine-4-sulfonyl chloride.

Example 78 N-trans-{4-[2-(4-Benzo(2,2-D2)-[1,3]dioxol-4-yl-piperazin-1-yl)-ethyl]-cyclohexyl}-2-(S)-[1,4]dioxan-2-yl-acetamide

The title compound, white solid (66.8 mg, 72.7%), MS (ISP) m/z=462.4 [(M+H)⁺], was prepared in accordance with the general method of example 1 from 4-[2-(4-Benzo(2,2-D2)-[1,3]dioxol-4-yl-piperazin-1-yl)-ethyl]-cyclohexylamine hydrochloride (Intermediate B) (70 mg, 189 μmol) and the chiral (S)-2-(1,4-dioxan-2-yl)acetic acid obtained from chiral separation of rac-[1,4]Dioxan-2-yl-acetic acid benzyl ester (using a Chiralpak AD column with 25% of EtOH in heptane) and hydrogenation to remove the benzyl ester.

Example 79 N-trans-{4-[2-(4-Benzo(2,2-D2) [1,3]dioxol-4-yl-piperazin-1-yl)-ethyl]-cyclohexyl}-2-methoxy-acetamide

The title compound, white solid (16.8 mg, 58.2%), MS (ISP) m/z=406.4 [(M+H)⁺], was prepared in accordance with the general method of example 1 from 4-[2-(4-Benzo(2,2-D2)-[1,3]dioxol-4-yl-piperazin-1-yl)-ethyl]-cyclohexylamine hydrochloride (Intermediate B) (25 mg, 67.6 μmol) and 2-methoxyacetic acid.

Example 80 N-trans-{4-[2-(4-Benzo(2,2-D2) [1,3]dioxol-4-yl-piperazin-1-yl)-ethyl]-cyclohexyl}-isobutyramide

The title compound, white solid (16.1 mg, 56.1%), MS (ISP) m/z=404.3 [(M+H)⁺], was prepared in accordance with the general method of example 1 from 4-[2-(4-Benzo(2,2-D2)-[1,3]dioxol-4-yl-piperazin-1-yl)-ethyl]-cyclohexylamine hydrochloride (Intermediate B) (25 mg, 67.6 μmol) and isobutyric acid.

Example 81 N-trans-{4-[2-(4-Benzo(2,2-D2)-[1,3]dioxol-4-yl-piperazin-1-yl)-ethyl]-cyclohexyl}-2-hydroxy-2-methyl-propionamide

The title compound, white solid (65.6 mg, 57.8%), MS (ISP) m/z=420.4 [(M+H)⁺], was prepared in accordance with the general method of example 1 from 4-[2-(4-Benzo(2,2-D2)-[1,3]dioxol-4-yl-piperazin-1-yl)-ethyl]-cyclohexylamine hydrochloride (Intermediate B) (95 mg, 257 μmol) and 2-hydroxy-2-methylpropanoic acid.

Example 82 (R)—N-trans{4-[2-(4-Benzo(2,2-D2)-[1,3]dioxol-4-yl-piperazin-1-yl)-ethyl]-cyclohexyl}-2-methoxypropanamide

The title compound, white solid (57.9 mg, 69.3%), MS (ISP) m/z=420.3 [(M+H)⁺], was prepared in accordance with the general method of example 1 from 4-[2-(4-Benzo(2,2-D2)-[1,3]dioxol-4-yl-piperazin-1-yl)-ethyl]-cyclohexylamine hydrochloride (Intermediate B) (70 mg, 189 μmol) and (R)-2-methoxypropanoic acid. Biochemical assay

The ability of the compounds to bind to the 5-HT_(2A), D₃ and D₂ receptors was determined using radioligand binding to cloned receptors selectively expressed in HEK-293 EBNA cells.

Membrane Preparation

HEK293 EBNA cells were transiently transfected with expression plasmids encoding for the human D₂ or D₃ or for the human 5-HT_(2A) receptor, respectively. The cells were harvested 48 h post-transfection, washed three times with cold PBS and stored at −80° C. prior to use. The pellet was suspended in cold 50 mM Tris-HCl buffer containing 10 mM EDTA (pH 7.4) and was homogenized with a Polytron (Kinematica AG, Basel, Switzerland) for 20-30 sec at 12.000 rpm. After centrifugation at 48.000×g for 30 min at 4° C., the pellet was resuspended in cold 10 mM Tris-HCl buffer containing 0.1 mM EDTA (pH 7.4), homogenized, and centrifuged as above. This pellet was further resuspended in a smaller volume of ice cold 10 mM Tris-HCl buffer containing 0.1 mM EDTA (pH 7.4) and homogenized with a Polytron for 20-30 sec at 12.000 rpm. The protein content of this homogenate was determined with the Bio-Rad (Bradford) Protein Assay (Biorad Laboratories GmbH, München, Germany) according to the instructions of the manufacturer using gamma globulin as the standard. This homogenate was stored at −80° C. in aliquots and thawed immediately prior to use.

Radioligand Binding Assay

Aliquots of membrane preparations were thawed at RT, resupended in assay buffer (D₂, D₃: 50 mM Tris-HCl, 120 mM NaCl, 5 mM MgCl₂, 1 mM EDTA, 5 mM KCl, 1.5 mM CaCl₂, pH=7.4; 5-HT_(2A): 50 mM Tris-HCl, 10 mM MgCl₂, 1 mM EGTA, pH=7.4), homogenized with a Polytron for 20-30 sec at 12.000 rpm and adjusted to a final concentration of approximately 7.5 μg protein/well (D₂, D₃) and 15 μg protein/well (5-HT_(2A)), respectively.

The binding affinity (K_(i)) of the compounds was determined using radioligand binding. Membranes were incubated in a total volume of 200 μl with a fixed concentration of radioligand (final concentration approximately 0.7 nM [³H]-spiperone for D₂, 0.5 nM [³H]-spiperone for D₃, and 1.1 nM [³H]-ketanserin for 5-HT_(2A)) and ten concentrations of test compound in ranging between 10 μM-0.1 nM for 1 h at RT. At the end of the incubation, the reaction mixtures were filtered on to unifilter 96-well white microplates with bonded GF/C filters (Packard BioScience, Zürich, Switzerland; preincubated for 1 h in 0.1% polyethylenimine (PEI) in assay buffer) with a Filtermate 196 harvester (Packard BioScience) and washed 3 times with cold assay buffer. The nonspecific binding was determined with equally composed reaction mixtures in the presence of 10 μM unlabelled spiperone. Per well 45 μl of Microscint 40 (Perkin Elmer, Schwerzenbach, Switzerland) was added, plates for sealed, shaken for 20 min and counted for 3 min on a Topcount Microplate Scintillation Counter (Canberra Packard SA, Zürich, Switzerland) with quenching correction.

Data Calculation

The CPM value for each duplicate of a concentration of competing compound was averaged (y1), then the % specific binding was calculated according to the equation (((y1−non-specific)/(total binding−non-specific))×100). Graphs were plotted with the % specific binding using XLfit, a curve fitting program that iteratively plots the data using Levenberg-Marquardt algorithm. The single site competition analysis equation used was y=A+((B−A)/(1+((x/C)D))), where y is the % specific binding, A is the minimum y, B is the maximum y, C is the IC₅₀, x is the log 10 of the concentration of the competing compound and D is the slope of the curve (the Hill Coefficient). From these curves the IC₅₀ (inhibition concentration at which 50% specific binding of the radioligand was displaced) and Hill coefficient were determined. The affinity constant (Ki) was calculated using the Cheng-Prusoff equation K_(i)=(IC₅₀/1+([L]/K_(d)), where [L] is the concentration of radioligand and K_(d) is the dissociation constant of the radioligand at the receptor as determined by the saturation isotherm.

The compounds of the present invention are selective dual modulators of the 5-HT_(2A) and D₃ receptors as is shown in table 1 below. Examples were tested in the above assay and found to have K_(i) 5-HT_(2A) values of about 0.1 nM to about 1 μM and K_(i) D₃ values of about 0.1 nM to about 1 μM. Particular compounds of formula (I) were found to have K_(i) 5-HT_(2A) values of about 1 nM to about 100 nM and K_(i) D₃ values of about 1 nM to about 200 nM. Most particular compounds of formula (I) were found to have K_(i) 5-HT_(2A) values of about 1 nM to about 35 nM and K_(i) D₃ values of about 1 nM to about 30 nM.

Particular compounds of formula (I) were found to bind more selectively to 5-HT_(2A) receptor than D₂ receptor by a factor of 5 or more, more particularly 10 or more, most particularly 25 or more. Particular compounds of formula (I) were found to bind more selectively to D₃ receptor than D₂ receptor by a factor of 5 or more, more particularly 10 or more, most particularly 50 or more.

TABLE 1 Binding affinities to HEK293 EBNA cells expressing human (h) receptors of representative examples. D₃ Ki 5HT_(2a) Ki D₂ Ki Ex [nM] [nM] [nM] 1 1.15 16.33 67.35 2 1.88 21.21 173.34 3 2.56 11.78 197.58 4 2.85 7.78 301.03 5 2.51 12.26 172.17 6 3.10 16.59 188.71 7 1.28 13.63 74.48 8 1.23 12.41 141.87 9 4.37 12.21 238.22 10 1.69 12.43 183.57 11 9.99 18.47 269.17 12 1.29 20.96 68.55 13 1.34 23.08 314.12 14 0.91 18.71 75.98 15 3.48 16.63 159.74 16 1.57 25.79 91.22 17 1.81 16.79 136.57 18 2.28 24.64 132.77 19 1.58 28.47 143.65 20 2.55 26.76 143.98 21 2.76 24.31 181.28 22 2.06 19.42 105.93 23 2.50 27.01 182.55 24 8.80 5.79 181.01 25 21.39 33.96 250.30 26 4.90 6.89 150.42 27 1.56 22.44 76.78 28 1.40 25.53 94.57 29 1.88 7.77 61.45 30 3.50 34.78 219.64 31 3.43 11.98 310.25 32 2.99 26.23 136.98 33 3.92 24.39 183.73 34 3.10 33.26 145.23 35 6.00 5.98 84.94 36 11.03 3.72 123.97 37 15.69 4.69 175.40 38 12.46 25.84 122.13 39 5.77 34.73 90.15 40 14.80 22.49 73.41 41 12.48 18.22 250.97 42 2.17 8.78 89.81 43 4.48 7.74 218.89 44 12.51 12.32 116.64 45 35.10 117.83 1510.24 46 3.79 28.74 82.51 47 2.40 13.88 509.13 48 1.79 11.42 88.19 49 4.59 10.65 4818.65 50 0.87 6.41 572.43 51 2.11 51.60 680.96 52 3.56 4.30 58.95 53 2.09 26.37 138.86 54 1.97 22.63 91.14 55 1.45 22.06 95.38 56 3.37 29.79 752.51 57 24.95 15.29 62.94 58 6.82 15.63 81.08 59 3.55 22.08 101.02 60 2.98 23.75 81.06 61 4.63 16.03 38.06 62 14.27 6.27 86.54 63 27.44 11.13 116.62 64 14.74 24.14 89.50 65 19.90 42.11 111.52 66 1.88 31.51 73.84 67 2.88 64.10 72.43 68 2.20 57.32 46.18 69 2.25 67.97 55.32 70 4.91 35.50 113.43 71 2.01 28.75 241.28 72 11.25 45.33 30.42 73 1.83 31.29 123.11 74 2.44 24.97 116.67 75 1.04 58.75 157.94 76 3.36 21.62 127.71 77 1.29 32.65 62.99 78 2.46 13.41 197.85 79 4.98 24.37 145.84 80 2.23 16.68 105.31 81 6.28 5.03 97.16 82 5.73 9.49 148.44 

1. A compound of formula (I)

wherein n is 0, 1, 2 or 3; Y is —C(O)— or —S(O)₂—; R¹ is hydrogen, halogen, cyano, alkyl, haloalkyl, hydroxy, alkoxy, haloalkoxy, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, —NR⁷R⁸, —C(O)—NR⁷R⁸, or —S(O)₂—R⁷; wherein alkyl, haloalkyl, and alkoxy are each optionally substituted by one, two or three independent R⁵; and wherein cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are each optionally substituted by one, two or three independent R⁶; R², R³ and R⁴ are each independently hydrogen, halogen, alkyl, haloalkyl, hydroxy, alkoxy or haloalkoxy; R⁵ is cyano, hydroxy, alkoxy, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, wherein cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are each optionally substituted by one, two or three independent R⁶; R⁶ is halogen, cyano, alkyl, haloalkyl, hydroxyalkyl, hydroxy, alkoxy, haloalkoxy, oxo, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; R⁷ and R⁸ are each independently hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl, aryl, aryl substituted by halogen, or heteroaryl; or a pharmaceutically acceptable salt or ester thereof; or a deuterated analog thereof.
 2. The compound of claim 1, wherein n is 0, 1, 2 or 3; Y is —C(O)— or —S(O)₂—; R¹ is hydrogen, cyano, alkyl, haloalkyl, hydroxy, alkoxy, haloalkoxy, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, —NR⁷R⁸, —C(O)—NR⁷R⁸, or —S(O)₂—R⁷; wherein alkyl, haloalkyl, and alkoxy are each optionally substituted by one, two or three independent R⁵; and wherein cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are each optionally substituted by one, two or three independent R⁶; R², R³ and R⁴ are each independently hydrogen, halogen, alkyl, haloalkyl, hydroxy, alkoxy or haloalkoxy; R⁵ is cyano, hydroxy, alkoxy, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, wherein cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are each optionally substituted by one, two or three independent R⁶; R⁶ is halogen, cyano, alkyl, haloalkyl, hydroxy, alkoxy, haloalkoxy, oxo, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; R⁷ and R⁸ are each independently hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl, aryl, or heteroaryl; or a pharmaceutically acceptable salt or ester thereof.
 3. The compound of claim 1, having formula (Ia)

or a pharmaceutically acceptable salt or ester thereof.
 4. The compound of claim 1, wherein n is 0 or
 1. 5. The compound of claim 1, wherein Y is —C(O)—.
 6. The compound of claim 1, wherein Y is —S(O)₂—.
 7. The compound of claim 1, wherein R¹ is hydrogen, halogen, cyano, alkyl, haloalkyl, hydroxy, alkoxy, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, —NR⁷R⁸, or —S(O)₂—R⁷; wherein alkyl is optionally substituted by one, two or three independent R⁵; and wherein cycloalkyl, heterocycloalkyl, aryl and heteroaryl are each optionally substituted by one, two or three independent R⁶.
 8. The compound of claim 1, wherein R¹ is hydrogen, fluoro, cyano, ethyl, hydroxy-ethyl, methoxy-ethyl, hydroxy-n-propyl, isopropyl, hydroxy-isopropyl, methoxy-isopropyl, hydroxyl-isobutyl, methoxy-isobutyl, trifluoromethyl, hydroxy, methoxy, cyclopropyl, difluoro-cyclopropyl, hydroxy-cyclopropyl, methoxy-cyclopropyl, cyclobutyl, chloro-cyclobutyl, hydroxy-cyclobutyl, hydroxymethyl-cyclobutyl, cyclopentyl, hydroxy-cyclopentyl, methoxy-cyclopentyl, cyclohexyl, hydroxy-cyclohexyl, methoxy-cyclohexyl, oxetanyl, methyl-oxetanyl, tetrahydrofuranyl, tetrahydro-1,6-thiophenyl, 1,1-dioxo-tetrahydro-1,6-thiophenyl, tetrahydropyranyl, piperazinyl, methyl-piperazinyl, piperidinyl, methyl-piperidinyl, morpholinyl, dioxanyl, phenyl, fluoro-phenyl, cyano-phenyl, morpholinyl-phenyl, isoxazolyl, methyl-isoxazolyl, imidazolyl, methyl-imidazolyl, pyridinyl, 2,3-dihydro-indolyl, benzo[1,3]dioxolyl, quinolinyl, chromanyl, 2,3-dihydro-benzo[1,4]dioxinyl, chlorophenylamine, dimethylamine, or methylsulfonyl.
 9. The compound of claim 1, wherein R², R³ and R⁴ are hydrogen.
 10. The compound of claim 1, wherein R⁵ is hydroxy or alkoxy.
 11. The compound of claim 1, wherein R⁶ is halogen, cyano, alkyl, hydroxyalkyl, hydroxy, alkoxy, oxo or heterocycloalkyl.
 12. The compound of claim 11, wherein R⁶ is fluoro, chloro, cyano, methyl, hydroxymethyl, hydroxy, methoxy, oxo or morpholinyl.
 13. The compound of claim 1, wherein R⁷ and R⁸ are each independently selected from hydrogen, alkyl, and aryl substituted by halogen.
 14. The compound of claim 13, wherein R⁷ and R⁸ are each independently selected from hydrogen, methyl, and chlorophenyl.
 15. The compound of claim 1, selected from the group consisting of: Trans-N-{4-[2-(4-Benzo[1,3]dioxol-4-yl-piperazin-1-yl)-ethyl]-cyclohexyl}-acetamide; Trans-N-{4-[2-(4-Benzo[1,3]dioxol-4-yl-piperazin-1-yl)-ethyl]-cyclohexyl}-3-methoxy-propionamide; Trans-N-{4-[2-(4-Benzo[1,3]dioxol-4-yl-piperazin-1-yl)-ethyl]-cyclohexyl}-2-[1,4]dioxan-2-yl-acetamide; Trans-N-{4-[2-(4-Benzo[1,3]dioxol-4-yl-piperazin-1-yl)-ethyl]-cyclohexyl}-2-(S)-[1,4]dioxan-2-yl-acetamide; Trans-N-{4-[2-(4-Benzo[1,3]dioxol-4-yl-piperazin-1-yl)-ethyl]-cyclohexyl}-2-(R)-[1,4]dioxan-2-yl-acetamide; Trans-N-{4-[2-(4-Benzo[1,3]dioxol-4-yl-piperazin-1-yl)-ethyl]-cyclohexyl}-2-(tetrahydro-furan-2-yl)-acetamide; Trans-N-{4-[2-(4-Benzo[1,3]dioxol-4-yl-piperazin-1-yl)-ethyl]-cyclohexyl}-propionamide; Trans-N-{4-[2-(4-Benzo[1,3]dioxol-4-yl-piperazin-1-yl)-ethyl]-cyclohexyl}-2-cyclopropyl-acetamide; Trans-N-{4-[2-(4-Benzo[1,3]dioxol-4-yl-piperazin-1-yl)-ethyl]-cyclohexyl}-2-methoxy-acetamide; Trans-N-{4-[2-(4-Benzo[1,3]dioxol-4-yl-piperazin-1-yl)-ethyl]-cyclohexyl}-2-hydroxy-acetamide; and Trans-N-{4-[2-(4-Benzo[1,3]dioxol-4-yl-piperazin-1-yl)-ethyl]-cyclohexyl}-benzamide; or a pharmaceutically acceptable salt or ester thereof.
 16. The compound of claim 1, selected from the group consisting of: Trans-{4-[2-(4-Benzo[1,3]dioxol-4-yl-piperazin-1-yl)-ethyl]-cyclohexyl}-carbamic acid methyl ester; Trans-N-{4-[2-(4-Benzo[1,3]dioxol-4-yl-piperazin-1-yl)-ethyl]-cyclohexyl}-2-(3-methyl-isoxazol-5-yl)-acetamide; Trans-N-{4-[2-(4-Benzo[1,3]dioxol-4-yl-piperazin-1-yl)-ethyl]-cyclohexyl}-2-cyano-acetamide; Trans-N-{4-[2-(4-Benzo[1,3]dioxol-4-yl-piperazin-1-yl)-ethyl]-cyclohexyl}-2-(1-hydroxy-cyclohexyl)-acetamide; Trans-N-{4-[2-(4-Benzo[1,3]dioxol-4-yl-piperazin-1-yl)-ethyl]-cyclohexyl}-3,3,3-trifluoro-propionamide; Trans-N-{4-[2-(4-Benzo[1,3]dioxol-4-yl-piperazin-1-yl)-ethyl]-cyclohexyl}-isobutyramide; Trans-N-{4-[2-(4-Benzo[1,3]dioxol-4-yl-piperazin-1-yl)-ethyl]-cyclohexyl}-3-methyl-butyramide; Trans-N-{4-[2-(4-Benzo[1,3]dioxol-4-yl-piperazin-1-yl)-ethyl]-cyclohexyl}-butyramide; Trans-2,2-Difluoro-cyclopropanecarboxylic acid {4-[2-(4-benzo[1,3]dioxol-4-yl-piperazin-1-yl)-ethyl]-cyclohexyl}-amide; Trans-N-{4-[2-(4-Benzo[1,3]dioxol-4-yl-piperazin-1-yl)-ethyl]-cyclohexyl}-3-methoxy-butyramide; and Trans-N-{4-[2-(4-Benzo[1,3]dioxol-4-yl-piperazin-1-yl)-ethyl]-cyclohexyl}-2-oxetan-3-yl-acetamide; or a pharmaceutically acceptable salt or ester thereof.
 17. The compound of claim 1, selected from the group consisting of: Trans-N-{4-[2-(4-Benzo[1,3]dioxol-4-yl-piperazin-1-yl)-ethyl]-cyclohexyl}-2-((1R,3R)-3-methoxy-cyclopentyl)-acetamide; Trans-N-{4-[2-(4-Benzo[1,3]dioxol-4-yl-piperazin-1-yl)-ethyl]-cyclohexyl}-2-hydroxy-2-methyl-propionamide; Trans-(S)—N-{4-[2-(4-Benzo[1,3]dioxol-4-yl-piperazin-1-yl)-ethyl]-cyclohexyl}-2-methoxy-propionamide; Trans-(R)—N-{4-[2-(4-Benzo[1,3]dioxol-4-yl-piperazin-1-yl)-ethyl]-cyclohexyl}-2-methoxy-propionamide; Trans-N-{4-[2-(4-Benzo[1,3]dioxol-4-yl-piperazin-1-yl)-ethyl]-cyclohexyl}-3-hydroxy-3-methyl-butyramide; Trans-N-{4-[2-(4-Benzo[1,3]dioxol-4-yl-piperazin-1-yl)-ethyl]-cyclohexyl}-2-(1-hydroxy-cyclobutyl)-acetamide; Trans-1-Hydroxy-cyclopropanecarboxylic acid {4-[2-(4-benzo[1,3]dioxol-4-yl-piperazin-1-yl)-ethyl]-cyclohexyl}-amide; Trans-N-{4-[2-(4-Benzo[1,3]dioxol-4-yl-piperazin-1-yl)-ethyl]-cyclohexyl}-2-(S)-tetrahydro-pyran-2-yl-acetamide; Trans-N-{4-[2-(4-Benzo[1,3]dioxol-4-yl-piperazin-1-yl)-ethyl]-cyclohexyl}-2-(R)-tetrahydro-pyran-2-yl-acetamide; Trans-N-{4-[2-(4-Benzo[1,3]dioxol-4-yl-piperazin-1-yl)-ethyl]-cyclohexyl}-2-(S)-tetrahydro-pyran-3-yl-acetamide; Trans-N-{4-[2-(4-Benzo[1,3]dioxol-4-yl-piperazin-1-yl)-ethyl]-cyclohexyl}-2-(R)-tetrahydro-pyran-3-yl-acetamide; and Trans-N-{4-[2-(4-Benzo[1,3]dioxol-4-yl-piperazin-1-yl)-ethyl]-cyclohexyl}-methanesulfonamide; or a pharmaceutically acceptable salt or ester thereof.
 18. The compound of claim 1, selected from the group consisting of: 1-Hydroxy-cyclobutanecarboxylic acid-trans-N-{4-[2-(4-benzo[1,3]dioxol-4-yl-piperazin-1-yl)-ethyl]-cyclohexyl}-amide; 1-Hydroxy-cyclopentanecarboxylic acid-trans-N-{4-[2-(4-benzo[1,3]dioxol-4-yl-piperazin-1-yl)-ethyl]-cyclohexyl}-amide; 1-Hydroxy-cyclohexanecarboxylic acid-trans-N {4-[2-(4-benzo[1,3]dioxol-4-yl-piperazin-1-yl)-ethyl]-cyclohexyl}-amide; Trans-N-{4-[2-(4-Benzo[1,3]dioxol-4-yl-piperazin-1-yl)-ethyl]-cyclohexyl}-2-hydroxy-butyramide; (R)-trans-N-{4-[2-(4-Benzo[1,3]dioxol-4-yl-piperazin-1-yl)-ethyl]-cyclohexyl}-2-hydroxy-3-methyl-butyramide; (S)-trans-N-{4-[2-(4-Benzo[1,3]dioxol-4-yl-piperazin-1-yl)-ethyl]-cyclohexyl}-2-hydroxy-3-methyl-butyramide; 1-Methoxy-cyclohexanecarboxylic acid-trans-N-{4-[2-(4-benzo[1,3]dioxol-4-yl-piperazin-1-yl)-ethyl]-cyclohexyl}-amide; (R)-{4-[2-(4-Benzo[1,3]dioxol-4-yl-piperazin-1-yl)-ethyl]-cyclohexyl}-2-hydroxy-propionamide; Tetrahydro-pyran-4-carboxylic acid-trans-N-{4-[2-(4-benzo[1,3]dioxol-4-yl-piperazin-1-yl)-ethyl]-cyclohexyl}-amide; Tetrahydro-furan-2-carboxylic acid-trans-N-{4-[2-(4-benzo[1,3]dioxol-4-yl-piperazin-1-yl)-ethyl]-cyclohexyl}-amide; Trans-N-{4-[2-(4-Benzo[1,3]dioxol-4-yl-piperazin-1-yl)-ethyl]-cyclohexyl}-4-morpholin-4-yl-benzamide; and Trans-N-{4-[2-(4-Benzo[1,3]dioxol-4-yl-piperazin-1-yl)-ethyl]-cyclohexyl}-4-fluoro-benzamide; or a pharmaceutically acceptable salt or ester thereof.
 19. The compound of claim 1, selected from the group consisting of: Quinoline-4-carboxylic acid-trans-N-{4-[2-(4-benzo[1,3]dioxol-4-yl-piperazin-1-yl)-ethyl]-cyclohexyl}-amide; Trans-N-{4-[2-(4-Benzo[1,3]dioxol-4-yl-piperazin-1-yl)-ethyl]-cyclohexyl}-nicotinamide; 2,3-Dihydro-benzo[1,4]dioxine-6-carboxylic acid-trans-N-{4-[2-(4-benzo[1,3]dioxol-4-yl-piperazin-1-yl)-ethyl]-cyclohexyl}-amide; Chroman-3-carboxylic acid-trans-N-{4-[2-(4-benzo[1,3]dioxol-4-yl-piperazin-1-yl)-ethyl]-cyclohexyl}-amide; 2-Benzo[1,3]dioxol-5-yl-trans-N-{4-[2-(4-benzo[1,3]dioxol-4-yl-piperazin-1-yl)-ethyl]-cyclohexyl}-acetamide; 1,1-Dioxo-tetrahydro-1,6-thiophene-3-carboxylic acid-trans-N-{4-[2-(4-benzo[1,3]dioxol-4-yl-piperazin-1-yl)-ethyl]-cyclohexyl}-amide; N-trans-{4-[2-(4-Benzo[1,3]dioxol-4-yl-piperazin-1-yl)-ethyl]-cyclohexyl}-2-(tetrahydro-pyran-4-yl)-acetamide; Cyclobutanecarboxylic acid-trans-N-{4-[2-(4-benzo[1,3]dioxol-4-yl-piperazin-1-yl)-ethyl]-cyclohexyl}-amide; Trans-N-{4-[2-(4-Benzo[1,3]dioxol-4-yl-piperazin-1-yl)-ethyl]-cyclohexyl}-2-methanesulfonyl-acetamide; Trans-N-{4-[2-(4-Benzo[1,3]dioxol-4-yl-piperazin-1-yl)-ethyl]-cyclohexyl}-2-(4-methoxy-cyclohexyl)-acetamide; 1-Methyl-piperidine-4-carboxylic acid-trans-N-{4-[2-(4-benzo[1,3]dioxol-4-yl-piperazin-1-yl)-ethyl]-cyclohexyl}-amide; and 3-Methyl-oxetane-3-carboxylic acid-trans-N-{4-[2-(4-benzo[1,3]dioxol-4-yl-piperazin-1-yl)-ethyl]-cyclohexyl}-amide; or a pharmaceutically acceptable salt or ester thereof.
 20. The compound of claim 1, selected from the group consisting of: Trans-N-{4-[2-(4-Benzo[1,3]dioxol-4-yl-piperazin-1-yl)-ethyl]-cyclohexyl}-4-cyano-benzamide; 3-Chloro-cyclobutanecarboxylic acid-trans-N-{4-[2-(4-benzo[1,3]dioxol-4-yl-piperazin-1-yl)-ethyl]-cyclohexyl}-amide; Trans-N-{4-[2-(4-Benzo[1,3]dioxol-4-yl-piperazin-1-yl)-ethyl]-cyclohexyl}-2-(4-methyl-piperazin-1-yl)-acetamide; 1-Methoxy-cyclopropanecarboxylic acid-trans-N-{4-[2-(4-benzo[1,3]dioxol-4-yl-piperazin-1-yl)-ethyl]-cyclohexyl}-amide; Trans-N-{4-[2-(4-Benzo[1,3]dioxol-4-yl-piperazin-1-yl)-ethyl]-cyclohexyl}-2-methoxy-2-methyl-propionamide; R-trans-N-{4-[2-(4-Benzo[1,3]dioxol-4-yl-piperazin-1-yl)-ethyl]-cyclohexyl}-2-methoxy-3-methyl-butyramide; (S)-trans-N-{4-[2-(4-Benzo[1,3]dioxol-4-yl-piperazin-1-yl)-ethyl]-cyclohexyl}-2-methoxy-3-methyl-butyramide; 2,2,2-Trifluoro-ethanesulfonic acid-trans-N-{4-[2-(4-benzo[1,3]dioxol-4-yl-piperazin-1-yl)-ethyl]-cyclohexyl}-amide; N-trans {4-[2-(4-Benzo[1,3]dioxol-4-yl-piperazin-1-yl)-ethyl]-cyclohexyl}-benzenesulfonamide; N-trans-{4-[2-(4-Benzo[1,3]dioxol-4-yl-piperazin-1-yl)-ethyl]-cyclohexyl}-4-fluoro-benzenesulfonamide; 1-Methyl-1H-imidazole-4-sulfonic acid-trans-N-{4-[2-(4-benzo[1,3]dioxol-4-yl-piperazin-1-yl)-ethyl]-cyclohexyl}-amide; and N-trans-{4-[2-(4-Benzo[1,3]dioxol-4-yl-piperazin-1-yl)-ethyl]-cyclohexyl}-2,2,2-trifluoro-acetamide; or a pharmaceutically acceptable salt or ester thereof.
 21. The compound of claim 1, selected from the group consisting of: 2,3-Dihydro-indole-1-carboxylic acid-trans-N-{4-[2-(4-benzo[1,3]dioxol-4-yl-piperazin-1-yl)-ethyl]-cyclohexyl}-amide; N-trans-3-{4-[2-(4-Benzo[1,3]dioxol-4-yl-piperazin-1-yl)-ethyl]-cyclohexyl}-1,1-dimethyl-urea; N-trans-{4-[2-(4-Benzo[1,3]dioxol-4-yl-piperazin-1-yl)-ethyl]-cyclohexyl}-2-fluoro-acetamide; N-trans-{4-[2-(4-Benzo[1,3]dioxol-4-yl-piperazin-1-yl)-ethyl]-cyclohexyl}-2-(3-hydroxymethyl-cyclobutyl)-acetamide; N-trans-1{4-[2-(4-Benzo[1,3]dioxol-4-yl-piperazin-1-yl)-ethyl]-cyclohexyl}-3-(4-chloro-phenyl)-urea; N-trans-{4-[2-(4-benzo[1,3]dioxol-4-yl-piperazin-1-yl)-ethyl]-cyclohexyl}-N,N-dimethyl-sulfamide; Morpholine-4-sulfonic acid-trans-N-{4-[2-(4-benzo[1,3]dioxol-4-yl-piperazin-1-yl)-ethyl]-cyclohexyl}-amide; Trans-N-{4-[2-(4-Benzo(2,2-D2)-[1,3]dioxol-4-yl-piperazin-1-yl)-ethyl]-cyclohexyl}-2-(S)-[1,4]dioxan-2-yl-acetamide; N-trans {4-[2-(4-Benzo(2,2-D2)[1,3]dioxol-4-yl-piperazin-1-yl)-ethyl]-cyclohexyl}-2-methoxy-acetamide; N-trans {4-[2-(4-Benzo(2,2-D2)[1,3]dioxol-4-yl-piperazin-1-yl)-ethyl]-cyclohexyl}-isobutyramide; N-trans {4-[2-(4-Benzo(2,2-D2)-[1,3]dioxol-4-yl-piperazin-1-yl)-ethyl]-cyclohexyl}-2-hydroxy-2-methyl-propionamide; and R—N-trans {4-[2-(4-Benzo(2,2-D2)-[1,3]dioxol-4-yl-piperazin-1-yl)-ethyl]-cyclohexyl}-2-methoxypropanamide; or a pharmaceutically acceptable salt or ester thereof.
 22. The compound of claim 1, selected from the group consisting of: Trans-N-{4-[2-(4-Benzo[1,3]dioxol-4-yl-piperazin-1-yl)-ethyl]-cyclohexyl}-2-[1,4]dioxan-2-yl-acetamide; Trans-N-{4-[2-(4-Benzo[1,3]dioxol-4-yl-piperazin-1-yl)-ethyl]-cyclohexyl}-2-(S)-[1,4]dioxan-2-yl-acetamide; Trans-N-{4-[2-(4-Benzo[1,3]dioxol-4-yl-piperazin-1-yl)-ethyl]-cyclohexyl}-2-methoxy-acetamide; Trans-N-{4-[2-(4-Benzo[1,3]dioxol-4-yl-piperazin-1-yl)-ethyl]-cyclohexyl}-2-hydroxy-acetamide; Trans-N-{4-[2-(4-Benzo[1,3]dioxol-4-yl-piperazin-1-yl)-ethyl]-cyclohexyl}-benzamide; Trans-N-{4-[2-(4-Benzo[1,3]dioxol-4-yl-piperazin-1-yl)-ethyl]-cyclohexyl}-2-(3-methyl-isoxazol-5-yl)-acetamide; Trans-N-{4-[2-(4-Benzo[1,3]dioxol-4-yl-piperazin-1-yl)-ethyl]-cyclohexyl}-2-(1-hydroxy-cyclohexyl)-acetamide; Trans-N-{4-[2-(4-Benzo[1,3]dioxol-4-yl-piperazin-1-yl)-ethyl]-cyclohexyl}-2-hydroxy-2-methyl-propionamide; Trans-(R)—N-{4-[2-(4-Benzo[1,3]dioxol-4-yl-piperazin-1-yl)-ethyl]-cyclohexyl}-2-methoxy-propionamide; Trans-N-{4-[2-(4-Benzo[1,3]dioxol-4-yl-piperazin-1-yl)-ethyl]-cyclohexyl}-2-(R)-tetrahydro-pyran-2-yl-acetamide; and Trans-N-{4-[2-(4-Benzo[1,3]dioxol-4-yl-piperazin-1-yl)-ethyl]-cyclohexyl}-methanesulfonamide; or a pharmaceutically acceptable salt of ester thereof.
 23. The compound of claim 1, selected from the group consisting of: 1-Hydroxy-cyclopentanecarboxylic acid-trans-N-{4-[2-(4-benzo[1,3]dioxol-4-yl-piperazin-1-yl)-ethyl]-cyclohexyl}-amide; 1-Hydroxy-cyclohexanecarboxylic acid-trans-N {4-[2-(4-benzo[1,3]dioxol-4-yl-piperazin-1-yl)-ethyl]-cyclohexyl}-amide; Tetrahydro-pyran-4-carboxylic acid-trans-N-{4-[2-(4-benzo[1,3]dioxol-4-yl-piperazin-1-yl)-ethyl]-cyclohexyl}-amide; Quinoline-4-carboxylic acid-trans-N-{4-[2-(4-benzo[1,3]dioxol-4-yl-piperazin-1-yl)-ethyl]-cyclohexyl}-amide; 2,3-Dihydro-benzo[1,4]dioxine-6-carboxylic acid-trans-N-{4-[2-(4-benzo[1,3]dioxol-4-yl-piperazin-1-yl)-ethyl]-cyclohexyl}-amide; Chroman-3-carboxylic acid-trans-N-{4-[2-(4-benzo[1,3]dioxol-4-yl-piperazin-1-yl)-ethyl]-cyclohexyl}-amide; 2-Benzo[1,3]dioxol-5-yl-trans-N-{4-[2-(4-benzo[1,3]dioxol-4-yl-piperazin-1-yl)-ethyl]-cyclohexyl}-acetamide; Trans-N-{4-[2-(4-Benzo[1,3]dioxol-4-yl-piperazin-1-yl)-ethyl]-cyclohexyl}-2-(4-methoxy-cyclohexyl)-acetamide; Trans-N-{4-[2-(4-Benzo(2,2-D2)-[1,3]dioxol-4-yl-piperazin-1-yl)-ethyl]-cyclohexyl}-2-(S)-[1,4]dioxan-2-yl-acetamide; and N-trans {4-[2-(4-Benzo(2,2-D2)-[1,3]dioxol-4-yl-piperazin-1-yl)-ethyl]-cyclohexyl}-2-hydroxy-2-methyl-propionamide; or a pharmaceutically acceptable salt or ester thereof.
 24. A pharmaceutical composition comprising a therapeutically effective amount of a compound of formula (I)

wherein n is 0, 1, 2 or 3; Y is —C(O)— or —S(O)₂—; R¹ is hydrogen, halogen, cyano, alkyl, haloalkyl, hydroxy, alkoxy, haloalkoxy, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, —NR⁷R⁸, —C(O)—NR⁷R⁸, or —S(O)₂—R⁷; wherein alkyl, haloalkyl, and alkoxy are each optionally substituted by one, two or three independent R⁵; and wherein cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are each optionally substituted by one, two or three independent R⁶; R², R³ and R⁴ are each independently hydrogen, halogen, alkyl, haloalkyl, hydroxy, alkoxy or haloalkoxy; R⁵ is cyano, hydroxy, alkoxy, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, wherein cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are each optionally substituted by one, two or three independent R⁶; R⁶ is halogen, cyano, alkyl, haloalkyl, hydroxyalkyl, hydroxy, alkoxy, haloalkoxy, oxo, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; R⁷ and R⁸ are each independently hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl, aryl, aryl substituted by halogen, or heteroaryl; or a pharmaceutically acceptable salt or ester thereof; or a deuterated analog thereof and a pharmaceutically acceptable excipient. 